Compositions useful for treating disorders related to kit

ABSTRACT

Compounds and compositions useful for treating disorders related to mutant KIT are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/973,378, filed May 7, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/887,614, filed Oct. 20, 2015, now U.S. Pat. No.9,994,575, which is a continuation of U.S. application Ser. No.14/515,327, filed Oct. 15, 2014, now U.S. Pat. No. 9,200,002, whichclaims priority to U.S. Provisional Application No. 61/975,229, filedApr. 4, 2014; U.S. Provisional Application No. 61/931,204, filed Jan.24, 2014; and U.S. Provisional Application No. 61/892,086, filed Oct.17, 2013, the content of each of which is incorporated by reference inits entirety.

BACKGROUND

The invention relates to compounds and compositions useful for treatingdisorders related to KIT and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinaseexpressed on a wide variety of cell types. The KIT molecule contains along extracellular domain, a transmembrane segment, and an intracellularportion. The ligand for KIT is stem cell factor (SCF), whose binding tothe extracellular domain of KIT induces receptor dimerization andactivation of downstream signaling pathways. KIT mutations generallyoccur in the DNA encoding the juxtumembrane domain (exon 11). They alsooccur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18.Mutations make KIT function independent of activation by SCF, leading toa high cell division rate and possibly genomic instability. Mutant KIThas been implicated in the pathogenesis of several disorders andconditions including systemic mastocytosis, GIST (gastrointestinalstromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma.As such, there is a need for therapeutic agents that inhibit KIT, andespecially agents that inhibit mutant KIT.

Platelet-derived growth factor receptors (PDGF-R) are cell surfacetyrosine kinase receptors for members of the platelet-derived growthfactor (PDGF) family. PDGF subunits -A and -B are important factorsregulating cell proliferation, cellular differentiation, cell growth,development and many diseases including cancer. A PDGFRA D842V mutationhas been found in a distinct subset of GIST, typically from the stomach.The D842V mutation is known to be associated with tyrosine kinaseinhibitor resistance. As such, there is a need for agents that targetthis mutation.

SUMMARY OF THE INVENTION

The present invention features compounds and compositions for treatingor preventing conditions such as mastocytosis and mast cell diseases bymodulating the activity of KIT, such compounds having the structuralFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from hydrogen or

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl or heterocyclyl;

each X and Y is independently selected from CR¹ or N;

Z is C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic orbicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl; whereineach of C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclicor bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic orbicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl isindependently substituted with 0-5 occurrences of R^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, or —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ heterocyclyl, halo, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic or bicyclic aralkyl,—N(R²)(R²), cyano, —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, heterocyclylalkyl is independently substituted with 0-5occurrences of R^(a); or 2 R^(C) together with the carbon atom(s) towhich they are attached form a cycloalkyl or heterocyclyl ringsubstituted with 0-5 occurrences of R^(a);

each R^(D) and R^(F) is, independently, hydrogen, C₁-C₆ alkyl, C₁-C₆cycloalkyl, hydroxyl, halo, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, —N(R²)(R²),or cyano;

each R¹ is independently selected from hydrogen, C₁-C₆ alkyl, monocyclicaralkyl, C₁-C₆ hydroxyalkyl, halo, C₁-C₆ haloalkyl, —N(R²)(R²), —OR²;

each R² is independently selected from hydrogen, hydroxyl, halo, thiol,C₁-C₆ thioalkyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, wherein each of C₁-C₆ alkyl, cycloalkyl andheterocyclyl is independently substituted with 0-5 occurrences of R^(b),or 2 R² together with the carbon or nitrogen atom to which they areattached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently hydrogen, halo, cyano, hydroxyl,C₁-C₆ alkoxyl, —C(O)R′, C(O)OR′, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, —NR′R′, or cycloalkyl, whereincycloalkyl is substituted with 0-5 occurrences of R′;

each R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl;

each R″ is hydrogen, C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyl, —C(O)—NR′R′;—C(S)—NR′R′; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

Any of the compounds disclosed herein may be used to treat any of thediseases disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a line graph depicting tumor growth curves of differenttreatment groups: vehicle

, Dasatinib at 25 mpk po bid*10 days (

), Compound 46 at 3 mpk po qd*10 days (

), Compound 46 at 10 mpk po qd*10 days (

), Compound 46 at 30 mpk po qd*10 days (

), and Compound 46 at 100 mpk po qd*10 days (

).

FIG. 2 is a line graph depicting the results from the body weightchanges in the tumor bearing mice of different treatment groups: vehicle(

, Dasatinib at 25 mpk po bid*10 days (

, Compound 46 at 3 mpk po qd*10 days (

), Compound 46 at 10 mpk po qd*10 days (

), Compound 46 at 30 mpk po qd*10 days (

), and Compound 46 at 100 mpk po qd*10 days (

).

DETAILED DESCRIPTION OF THE INVENTION

“Aliphatic group” means a straight-chain, branched-chain, or cyclichydrocarbon group and includes saturated and unsaturated groups, such asan alkyl group, an alkenyl group, and an alkynyl group.

“Alkylene” refers to a divalent radical of an alkyl group, e.g., —CH₂—,—CH₂CH₂—, and CH₂CH₂CH₂—.

“Alkenyl” means an aliphatic group containing at least one double bond.

“Alkoxyl” or “alkoxy” means an alkyl group having an oxygen radicalattached thereto. Representative alkoxyl groups include methoxy, ethoxy,propyloxy, tert-butoxy and the like. The term “haloalkoxy” refers to analkoxy in which one or more hydrogen atoms are replaced by halo, andincludes alkoxy moieties in which all hydrogens have been replaced byhalo (e.g., perfluoroalkoxy).

“Alkyl” refers to a monovalent radical of a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

“Alkenylene” refers to an alkenyl group having two connecting points.For example, “ethenylene” represents the group —CH═CH—. Alkenylenegroups can also be in an unsubstituted form or substituted form with oneor more substituents.

“Alkynyl” refers to a straight or branched hydrocarbon chain containing2-12 carbon atoms and characterized in having one or more triple bonds.Examples of alkynyl groups include, but are not limited to, ethynyl,propargyl, and 3-hexynyl. One of the triple bond carbons may optionallybe the point of attachment of the alkynyl substituent.

“Alkynylene” refers to an alkynyl having two connecting points. Forexample, “ethynylene” represents the group —C≡C—. Alkynylene groups canalso be in an unsubstituted form or substituted form with one or moresubstituents.

“Hydroxyalkylene” or “hydroxyalkyl” refers to an alkylene or alkylmoiety in which an alkylene or alkyl hydrogen atom is replaced by ahydroxyl group. Hydroxyalkylene or hydroxyalkyl includes groups in whichmore than one hydrogen atom has been replaced by a hydroxyl group.

“Aromatic ring system” is art-recognized and refers to a monocyclic,bicyclic or polycyclic hydrocarbon ring system, wherein at least onering is aromatic.

“Aryl” refers to a monovalent radical of an aromatic ring system.Representative aryl groups include fully aromatic ring systems, such asphenyl, naphthyl, and anthracenyl, and ring systems where an aromaticcarbon ring is fused to one or more non-aromatic carbon rings, such asindanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and thelike.

“Arylalkyl” or “aralkyl” refers to an alkyl moiety in which an alkylhydrogen atom is replaced by an aryl group. Aralkyl includes groups inwhich more than one hydrogen atom has been replaced by an aryl group.Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl,3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

“Aryloxy” refers to —O-(aryl), wherein the heteroaryl moiety is asdefined herein.

“Halo” refers to a radical of any halogen, e.g., —F, —Cl, —Br, or —I.

“Haloalkyl” and “haloalkoxy” refers to alkyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Haloalkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—, and—CH₂CH₂CH₂—, in which one or more hydrogen atoms are replaced by halo,and includes alkyl moieties in which all hydrogens have been replaced byhalo.

“Heteroalkyl” refers to an optionally substituted alkyl, which has oneor more skeletal chain atoms selected from an atom other than carbon,e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given, e.g. C₁-C₆ heteroalkyl which refers to thenumber of carbons in the chain, which in this example includes 1 to 6carbon atoms. For example, a —CH₂OCH₂CH₃ radical is referred to as a“C₃” heteroalkyl. Connection to the rest of the molecule may be througheither a heteroatom or a carbon in the heteroalkyl chain.“Heteroalkylene” refers to a divalent optionally substituted alkyl,which has one or more skeletal chain atoms selected from an atom otherthan carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinationsthereof.

“Carbocyclic ring system” refers to a monocyclic, bicyclic or polycyclichydrocarbon ring system, wherein each ring is either completelysaturated or contains one or more units of unsaturation, but where noring is aromatic.

“Carbocyclyl” refers to a monovalent radical of a carbocyclic ringsystem. Representative carbocyclyl groups include cycloalkyl groups(e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like),and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

“Cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclicnon-aromatic hydrocarbon groups having 3 to 12 carbons. Anysubstitutable ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkyl groups can contain fused or spiro rings.Fused rings are rings that share a common carbon atom. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

“Cycloalkylalkyl” refers to a -(cycloalkyl)-alkyl radical wherecycloalkyl and alkyl are as disclosed herein. The “cycloalkylalkyl” isbonded to the parent molecular structure through the cycloalkyl group.

“Heteroaromatic ring system” is art-recognized and refers to monocyclic,bicyclic or polycyclic ring system wherein at least one ring is botharomatic and comprises at least one heteroatom (e.g., N, O or S); andwherein no other rings are heterocyclyl (as defined below). In certaininstances, a ring which is aromatic and comprises a heteroatom contains1, 2, 3, or 4 ring heteroatoms in such ring.

“Heteroaryl” refers to a monovalent radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (i)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl; (ii) each ring is aromatic orcarbocyclyl, at least one aromatic ring comprises a heteroatom and atleast one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3-(4H)-one,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and(iii) each ring is aromatic or carbocyclyl, and at least one aromaticring shares a bridgehead heteroatom with another aromatic ring, e.g.,4H-quinolizinyl.

“Heterocyclic ring system” refers to monocyclic, bicyclic and polycyclicring systems where at least one ring is saturated or partiallyunsaturated (but not aromatic) and comprises at least one heteroatom. Aheterocyclic ring system can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted.

“Heterocyclyl” refers to a monovalent radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (i)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl;(ii) at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is an aromatic carbon ring, e.g.,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (iii)at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine. In some embodiments, heterocyclylcan include:

“Heterocyclylalkyl” refers to an alkyl group substituted with aheterocyclyl group.

“Cyano” refers to a —CN radical.

“Nitro” refers to —NO₂.

“Hydroxy” or “hydroxyl” refers to —OH.

“Hydroxyalkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—, and—CH₂CH₂CH₂—, in which one or more hydrogen atoms are replaced by ahydroxy, and includes alkyl moieties in which all hydrogens have beenreplaced by hydroxy.

“Substituted”, whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at each position. Combinations of substituents envisionedunder this invention are preferably those that result in the formationof stable or chemically feasible compounds. The term “stable”, as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound, as well as enantiomeric mixtures thereof.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

The compounds or compositions described herein may contain anenantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one formof the compound, e.g., the S-enantiomer. In other words such compoundsor compositions contain an enantiomeric excess of the S enantiomer overthe R enantiomer.

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example deuterium (²H), tritium (³H),carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of thecompounds disclosed herein, whether radioactive or not, are intended tobe encompassed within the scope of the present invention. In addition,all tautomeric forms of the compounds described herein are intended tobe within the scope of the invention.

The compound can be useful as the free base or as a salt. Representativesalts include the hydrobromide, hydrochloride, sulfate, bisulfate,phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts and the like. (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. The term “hydrate” or“hydrated” as used herein, refers to a compound formed by the union ofwater with the parent compound.

In general, the solvated forms are equivalent to unsolvated forms andare encompassed within the scope of the present invention. Certaincompounds disclosed herein may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present invention and are intended to be withinthe scope of the present invention.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyincludes humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

Compounds

In one embodiment, the invention provides a compound having structuralFormula I or a pharmaceutically acceptable salt thereof, wherein:

W is selected from hydrogen and

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl and heterocyclyl;

each X and Y is independently selected from CR¹ and N;

Z is C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic orbicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl; whereineach of C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclicor bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic orbicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl isindependently substituted with 0-5 occurrences of R^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, and —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ heterocyclyl, halo, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic or bicyclic aralkyl,—N(R²)(R²), cyano, and —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, heterocyclylalkyl is independently substituted with 0-5occurrences of R^(a); or 2 R^(C) together with the carbon atom(s) towhich they are attached form a cycloalkyl or heterocyclyl ringsubstituted with 0-5 occurrences of R^(a);

each R^(D) and R^(F) is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆ cycloalkyl, hydroxyl, halo, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,—N(R²)(R²), and cyano;

each R′ is independently selected from hydrogen, C₁-C₆ alkyl, monocyclicaralkyl, C₁-C₆ hydroxyalkyl, halo, C₁-C₆ haloalkyl, —N(R²)(R²), and—OR²;

each R² is independently selected from hydrogen, hydroxyl, halo, thiol,C₁-C₆ thioalkyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl, wherein each of C₁-C₆ alkyl, cycloalkyl andheterocyclyl is independently substituted with 0-5 occurrences of R^(b),or 2 R² together with the carbon or nitrogen atom to which they areattached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently selected from hydrogen, halo,cyano, hydroxyl, C₁-C₆ alkoxyl, —C(O)R′, C(O)OR′, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, —NR′R′, andcycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences ofR′;

each R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl;

each R″ is hydrogen, C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyl, —C(O)—NR′R′; or—C(S)—NR′R′; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

In some embodiments, W is H. In some embodiments, W is

In some embodiments, Ring A is monocyclic or bicyclic aryl substitutedwith 0, 1, 2 or 3 R^(A). In some embodiments, Ring A is phenyl. In someembodiments, Ring A is phenyl substituted with halo. In someembodiments, Ring A is phenyl substituted with fluoro or chloro. In someembodiments, Ring A is 4-fluorophenyl. In some embodiments, Ring A is2,4-difluorophenyl. In some embodiments, Ring A is2,4,6-trifluorophenyl. In some embodiments, Ring A is 4-chlorophenyl.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, R^(A) is independently selected from C₁-C₆alkyl and halo. In some embodiments, R^(A) is independently selectedfrom fluoro, chloro and methyl. In some embodiments, R^(A) isindependently selected from fluoro and chloro. In some embodiments,R^(A) is methyl. In some embodiments, R^(A) is fluoro and q is 1, 2, or3. In some embodiments, R^(A) is chloro and fluoro and q is 2. In someembodiments, R^(A) is methyl and fluoro and q is 2.

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, R^(B) is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl.In some embodiments, R^(B) is methyl, ethyl, or hydroxymethyl. In someembodiments, p is 0 or 1. In some embodiments, p is 0. In someembodiments, p is 1.

In some embodiments, at least one of X and Y is N. In some embodiments,X and Y are both N. In some embodiments, X and Y are both CR¹. In someembodiments, X and Y are both CH.

In some embodiments, Z is monocyclic or bicyclic aryl. In someembodiments, Z is monocyclic or bicyclic heteroaryl. In someembodiments, Z is monocyclic or bicyclic heterocyclyl. In someembodiments, Z is monocyclic heteroaryl. In some embodiments, Z isselected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl.In some embodiments, Z is substituted with 0, 1 or 2 occurrences ofR^(C). In some embodiments, Z is substituted with 0 or 1 occurrences ofR^(C).

In some embodiments, R^(C) is independently selected from cyano, C₁-C₆alkyl, C₁-C₆ alkynyl, halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—OC(O)R², —C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In someembodiments, R^(C) is independently selected from cyano, C₁-C₆ alkyl,halo, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In some embodiments,each R^(C) is independently selected from C₁-C₆ alkyl, halo, monocyclicand bicyclic heterocyclyl.

In some embodiments, R^(D) is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, —N(R²)(R²), or cyano. In some embodiments, R^(D) is hydrogenor —N(R²)(R²). In some embodiments, R^(D) is hydrogen or —NH².

In some embodiments, R^(F) is hydrogen or halo, e.g., chloro or fluoro.In some embodiments, R is hydrogen. In some embodiments, R^(F) is chloroor fluoro.

In some embodiments, L is selected from a bond, —(C(R²)(R²))_(m)—,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ hydroxyalkylene)-,—S—, —S(O), —SO₂—, and —N(R²)—. In some embodiments, L is selected froma bond, —(C(R²)(R²))_(m)—, —S—, and —SO₂—. In some embodiments, L is—(C(R²)(R²))_(m)—. In some embodiments, L is a bond or CH₂. In someembodiments, L is —(C(R²)(R²))_(m)—, wherein each R² is independentlyselected from hydrogen, hydroxyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, and cycloalkyl; and m is 1.

In some embodiments, each R² is independently selected from hydrogen,hydroxyl, halo, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, and cycloalkyl, wherein each of C₁-C₆ alkyl and cycloalkylis independently substituted with 0-5 occurrences of R^(b), or 2 R²together with the carbon or nitrogen atom to which they are attachedform a cycloalkyl or heterocyclyl ring. In some embodiments, each R² isindependently selected from halo, hydrogen, hydroxyl, —NR″R″, and C₁-C₆alkyl wherein C₁-C₆ alkyl is independently substituted with 0-5occurrences of R^(b). In some embodiments, R^(b) is independentlyhydrogen, halo or hydroxyl. In some embodiments, L is —NR″R″. In someembodiments, R″ is hydrogen or C₁-C₆ alkyl. In some embodiments, R″ ishydrogen. In some embodiments, L is —S—. In some embodiments, L is—CH₂—.

In some embodiments, m is 0, 1 or 2. In some embodiments, m is 1. Insome embodiments, m is 2.

In some embodiments, p is 0 or 1.

In some embodiments, q is 0, 1, 2 or 3. In some embodiments, q is 0. Insome embodiments, q is 1. In some embodiments, q is 2. In someembodiments, q is 3.

In another embodiment, the invention features a compound of Formula II,or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from monocyclic or bicyclic aryl, monocyclic orbicyclic heteroaryl, cycloalkyl and heterocyclyl;

Z is selected from C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl,monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl,monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclicheterocyclylalkyl; wherein each of C₁-C₆ alkyl, cycloalkyl, monocyclicor bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclicheterocyclylalkyl is independently substituted with 0-5 occurrences ofR^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, and —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ heterocyclyl, halo, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic or bicyclic aralkyl,—N(R²)(R²), cyano, and —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, heterocyclylalkyl is independently substituted with 0-5occurrences of R^(a); or 2 R^(C) together with the carbon atom(s) towhich they are attached form a cycloalkyl or heterocyclyl ringsubstituted with 0-5 occurrences of R^(a);

each R² is independently selected from hydrogen, hydroxyl, halo, thiol,C₁-C₆ thioalkyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl, wherein each of C₁-C₆ alkyl, cycloalkyl andheterocyclyl is independently substituted with 0-5 occurrences of R^(b),or 2 R² together with the carbon or nitrogen atom to which they areattached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently selected from hydrogen, halo,cyano, hydroxyl, C₁-C₆ alkoxyl, —C(O)R′, C(O)OR′, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, —NR′R′, andcycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences ofR′;

each R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl;

each R″ is hydrogen, C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyl, —C(O)—NR′R′;—C(S)—NR′R′; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

In some embodiments, A is monocyclic or bicyclic aryl. In someembodiments, Ring A is monocyclic or bicyclic aryl substituted with 0,1, 2 or 3 R^(A). In some embodiments, Ring A is phenyl. In someembodiments, Ring A is phenyl substituted with halo. In someembodiments, Ring A is phenyl substituted with fluoro or chloro. In someembodiments, Ring A is 4-fluorophenyl. In some embodiments, Ring A is2,4-difluorophenyl. In some embodiments, Ring A is2,4,6-trifluorophenyl. In some embodiments, Ring A is 4-chlorophenyl.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, R^(A) is independently selected from C₁-C₆alkyl and halo. In some embodiments, R^(A) is independently selectedfrom fluoro, chloro and methyl. In some embodiments, R^(A) isindependently selected from fluoro and chloro. In some embodiments,R^(A) is methyl. In some embodiments, R^(A) is fluoro and q is 1, 2, or3. In some embodiments, R^(A) is chloro and fluoro and q is 2. In someembodiments, R^(A) is methyl and fluoro and q is 2.

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, R^(B) is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl.In some embodiments, R^(B) is methyl, ethyl, or hydroxymethyl. In someembodiments, p is 0 or 1. In some embodiments, p is 0. In someembodiments, p is 1.

In some embodiments, Z is monocyclic or bicyclic aryl. In someembodiments, Z is monocyclic or bicyclic heteroaryl. In someembodiments, Z is monocyclic or bicyclic heterocyclyl. In someembodiments, Z is monocyclic heteroaryl. In some embodiments, Z isselected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl.In some embodiments, Z is substituted with 0, 1 or 2 occurrences ofR^(C). In some embodiments, Z is substituted with 0 or 1 occurrences ofR^(C).

In some embodiments, R^(C) is independently selected from cyano, C₁-C₆alkyl, C₁-C₆ alkynyl, halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—OC(O)R², —C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In someembodiments, R^(C) is independently selected from cyano, C₁-C₆ alkyl,halo, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In some embodiments,each R^(C) is independently selected from C₁-C₆ alkyl, halo, monocyclicor bicyclic heterocyclyl.

In some embodiments, R^(D) is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, —N(R²)(R²), or cyano. In some embodiments, R^(D) is hydrogenor —N(R²)(R²). In some embodiments, R^(D) is hydrogen or —NH².

In some embodiments, R^(F) is hydrogen or halo, e.g., chloro or fluoro.In some embodiments, R is hydrogen. In some embodiments, R^(F) is chloroor fluoro.

In some embodiments, L is selected from a bond, —(C(R²)(R²))_(m)—,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ hydroxyalkylene)-,—S—, —S(O), —SO₂—, and —N(R²)—. In some embodiments, L is selected froma bond, —(C(R²)(R²))_(m)—, —S—, and —SO₂—. In some embodiments, L is—(C(R²)(R²))_(m)—. In some embodiments, L is a bond or CH₂. In someembodiments, L is —(C(R²)(R²))_(m)—, wherein each R² is independentlyselected from hydrogen, hydroxyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, and cycloalkyl; and m is 1.

In some embodiments, each R² is independently selected from hydrogen,hydroxyl, halo, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, cycloalkyl, wherein each of C₁-C₆ alkyl and cycloalkyl isindependently substituted with 0-5 occurrences of R^(b), or 2 R²together with the carbon or nitrogen atom to which they are attachedform a cycloalkyl or heterocyclyl ring. In some embodiments, each R² isindependently selected from halo, hydrogen, hydroxyl, —NR″R″, C₁-C₆alkyl wherein C₁-C₆ alkyl is independently substituted with 0-5occurrences of R^(b). In some embodiments, R^(b) is independentlyhydrogen, halo or hydroxyl. In some embodiments, L is —NR″R″. In someembodiments, R″ is hydrogen or C₁-C₆ alkyl. In some embodiments, R″ ishydrogen. In some embodiments, L is —S—. In some embodiments, L is—CH₂—.

In some embodiments, m is 0, 1 or 2. In some embodiments, m is 1. Insome embodiments, m is 2.

In some embodiments, p is 0 or 1.

In some embodiments, q is 0, 1, 2 or 3. In some embodiments, q is 0. Insome embodiments, q is 1. In some embodiments, q is 2. In someembodiments, q is 3.

In another embodiment, the invention features a compound of Formula III,or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl,monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl,monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclicheterocyclylalkyl; wherein each of C₁-C₆ alkyl, cycloalkyl, monocyclicor bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclicheterocyclylalkyl is independently substituted with 0-5 occurrences ofR^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, and —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ heterocyclyl, halo, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic or bicyclic aralkyl,—N(R²)(R²), cyano, and —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, heterocyclylalkyl is independently substituted with 0-5occurrences of R^(a); or 2 R^(C) together with the carbon atom(s) towhich they are attached form a cycloalkyl or heterocyclyl ringsubstituted with 0-5 occurrences of R^(a);

each R² is independently selected from hydrogen, hydroxyl, halo, thiol,C₁-C₆ thioalkyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl, wherein each of C₁-C₆ alkyl, cycloalkyl andheterocyclyl is independently substituted with 0-5 occurrences of R^(b),or 2 R² together with the carbon or nitrogen atom to which they areattached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently selected from hydrogen, halo,cyano, hydroxyl, C₁-C₆ alkoxyl, —C(O)R′, C(O)OR′, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, —NR′R′, andcycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences ofR′;

each R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl;

each R″ is hydrogen, C₁-C₆ alkyl, —C(O)—C₁-C₆ alkyl, —C(O)—NR′R′;—C(S)—NR′R′; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, each R^(A) is independently selected fromC₁-C₆ alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²),cyano, —OR². In some embodiments, R^(A) is independently selected fromC₁-C₆ alkyl and halo. In some embodiments, R^(A) is independentlyselected from fluoro, chloro and methyl. In some embodiments, R^(A) ishalo. In some embodiments, R^(A) is independently selected from fluoroand chloro. In some embodiments, R^(A) is methyl. In some embodiments,R^(A) is fluoro and q is 1, 2, or 3. In some embodiments, R^(A) ischloro and fluoro and q is 2. In some embodiments, R^(A) is methyl andfluoro and q is 2.

In some embodiments, Z is monocyclic or bicyclic aryl. In someembodiments, Z is monocyclic or bicyclic heteroaryl. In someembodiments, Z is monocyclic or bicyclic heterocyclyl. In someembodiments, Z is monocyclic heteroaryl. In some embodiments, Z isselected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl.In some embodiments, Z is substituted with 0, 1 or 2 occurrences ofR^(C). In some embodiments, Z is substituted with 0 or 1 occurrences ofR^(C).

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, R^(B) is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl.In some embodiments, R^(B) is methyl, ethyl, or hydroxymethyl. In someembodiments, p is 0 or 1. In some embodiments, p is 0. In someembodiments, p is 1.

In some embodiments, R^(C) is independently selected from cyano, C₁-C₆alkyl, C₁-C₆ alkynyl, halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—OC(O)R², —C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In someembodiments, R^(C) is independently selected from cyano, C₁-C₆ alkyl,halo, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, —C(O)R²,—C(O)OR², —N(R²)(R²), —C(O)—N(R²)(R²), and —OR². In some embodiments,each R^(C) is independently selected from C₁-C₆ alkyl, halo, monocyclicor bicyclic heterocyclyl.

In some embodiments, L is selected from a bond, —(C(R²)(R²))_(m)—,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ hydroxyalkylene)-,—S—, —S(O), —SO₂—, and —N(R²)—. In some embodiments, L is selected froma bond, —(C(R²)(R²))_(m)—, —S—, and —SO₂—. In some embodiments, L is—(C(R²)(R²))_(m)—. In some embodiments, L is a bond or CH₂. In someembodiments, L is —(C(R²)(R²))_(m)—, wherein each R² is independentlyselected from hydrogen, hydroxyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, and cycloalkyl; and m is 1.

In some embodiments, q is 0, 1, 2 or 3. In some embodiments, q is 1, 2or 3.

The invention also features pharmaceutical compositions comprising apharmaceutically acceptable carrier and any compound of Formulas I-III.

The table below shows the structures of compounds described herein.

Compound Number Structure 1

2

4

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

95

96

97

94

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

Synthesis

Compounds of the invention, including salts and N-oxides thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below. The reactions for preparing compounds of theinvention can be carried out in suitable solvents which can be readilyselected by one of skill in the art of organic synthesis. Suitablesolvents can be substantially non-reactive with the starting materials(reactants), the intermediates, or products at the temperatures at whichthe reactions are carried out, e.g., temperatures which can range fromthe solvent's freezing temperature to the solvent's boiling temperature.A given reaction can be carried out in one solvent or a mixture of morethan one solvent. Depending on the particular reaction step, suitablesolvents for a particular reaction step can be selected by the skilledartisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: NewJersey, (2006), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC).

Indications

The compounds described herein can be useful for treating conditionsassociated with aberrant KIT activity, in humans or non-humans.Activating mutations in KIT are found in multiple indications, includingsystemic mastocytosis, GIST (gastrointestinal stromal tumors), AML(acute myeloid leukemia), melanoma, seminoma, intercranial germ celltumors, and mediastinal B-cell lymphoma.

Mastocytosis refers to a group of disorders characterized by excessivemast cell accumulation in one tissue, or in multiple tissues.Mastocytosis is subdivided into two groups of disorders: (1) cutaneousmastocytosis (CM) describes forms that are limited to the skin; and (2)systemic mastocytosis (SM) describes forms in which mast cellsinfiltrate extracutaneous organs, with or without skin involvement. SMis further subdivided into five forms: indolent (ISM), smoldering (SSM),aggressive (ASM), SM with associated hemotologic non-mast cell lineagedisease (SM-AHNMD), and mast cell leukemia (MCL).

Diagnosis of systemic mastocytosis is based in part on histological andcytological studies of bone marrow showing infiltration by mast cells offrequently atypical morphology, which frequently abnormally expressnon-mast cell markers (CD25 and/or CD2). Diagnosis of SM is confirmedwhen bone marrow mast cell infiltration occurs in the context of one ofthe following: (1) abnormal mast cell morphology (spindle-shaped cells);(2) elevated level of serum tryptase above 20 ng/mL; or (3) the presenceof the activating KIT D816V mutation.

Activating mutations at the D816 position are found in the vast majorityof mastocytosis cases (90-98%), with the most common mutations beingD816V and D816H, and D816Y. The D816V mutation is found in theactivation loop of the kinase domain, and leads to constitutiveactivation of KIT kinase.

The compounds described herein may also be useful to treat GIST.Complete surgical resection remains the principal treatment of choicefor patients with a primary GIST. Surgery is effective in approximately50% of patients with GIST; of the remaining patients, tumor recurrenceis frequent. Primary treatment with a KIT inhibitor such as imatinib hasalso been shown to be sufficient for initial treatment. However,resistance to imatinib occurs within months through somatic mutation.These secondary imatinib resistant mutations are most frequently locatedon Exon 11, 13, 14, 17 or 18. Sunitinib is the standard of care secondline treatment for most imatinib resistant tumors and is effective forthose containing mutations in exons 11, 13 and 14. However, secondaryKIT mutations in exons 17 and 18 are resistant to sunitinib treatmentand furthermore, tumors containing tertiary resistance mutations in exon17 and 18 emerge several months after sunitinib treatment. Regorafenibhas shown promising results in a phase 3 clinical trial of imatinib,sunitinib resistant GISTs with activity against several but not all exon17 and 18 mutations, of which D816 is one. Thus, there is a need fortherapeutic agents to treat GIST patients with exon 17 mutations notaddressed by regorafenib.

In addition to the use of the compounds described herein as singleagents in the refractory GIST setting, the use of combinations ofimatinib, sunitinib and/or regorafenib with the compounds disclosedherein may allow for the prevention of emergence of resistance to exon17 mutations.

There is a subset of GIST patients with a D842V mutation in PDGFRα; thissubgroup of GIST patients can be stratified by identifying thismutation. This subset of patients is refractory to all tyrosine kinaseinhibitors currently available. The compounds described herein, due totheir activity against PDGFRα D842V, can be useful in treating thesepatients.

The compounds described herein may also be useful in treating AML. AMLpatients harbor KIT mutations as well, with the majority of thesemutations at the D816 position.

In addition, mutations in KIT have been linked to Ewing's sarcoma, DLBCL(diffuse large B cell lymphoma), dysgerminoma, MDS (myelodysplasticsyndrome), NKTCL (nasal NK/T-cell lymphoma), CMML (chronicmyelomonocytic leukemia), and brain cancers.

The compounds disclosed herein may be used to treat conditionsassociated with the KIT mutations in Exon 9, Exon 11, Exon 13, Exon 14,Exon 17 and/or Exon 18. They may also be used to treat conditionsassociated with wild-type KIT. The compounds described herein may beused as single agents to treat the conditions described herein, or theymay be used in combination with other therapeutic agents, including,without limitation, imatinib, sunitinib and regorafenib. Other agentsinclude the compounds described in WO 2014/039714 and WO 2014/100620.

Compounds described herein can be active against one or more KITmutations in Exon 17 (e.g., D816V, D816Y, D816F, D816K, D816H, D816A,D816G, D820A, D820E, D820G, N822K, N822H, Y823D, and A829P), and muchless active against wild-type KIT. These compounds can be administeredin combination with an agent that is (a) active against other activatingmutations of KIT, such as Exon 9 and 11 mutations, but (b) not activeagainst the Exon 17 mutations. Such agents include imatinib, sunitinib,and regorafenib. The combination of the compound and the agent will thusinhibit Exon 17 mutant KIT, as well as inhibiting Exon 9/11 mutant KIT.The compound and agent can be co-administered, or administered in analternating regimen. That is, the Exon 17 mutant KIT inhibitor can beadministered alone for a period of time; then the Exon 9/11 mutant KITinhibitor can be administered alone for a period of time following. Thiscycle may then be repeated. It is believed that such a regimen couldslow the development of resistance to the Exon 17 mutant KIT inhibitorand/or the Exon 9/11 mutant KIT inhibitor.

In addition, compounds described herein that can be selective for Exon17 KIT mutations can be administered with agents that are active againstExon 9/11 mutations, in combination with a third agent that coversmutations that are missed with the two-way combo. The combination of thethree agents could inhibit a spectrum of KIT mutations, as well aswild-type KIT in some instances. The agents could be administeredsimultaneously, or in an alternating regimen. They can be administeredone at a time, or two agents can be administered together for a periodof time; then the third agent can be administered alone for a followingperiod of time. It is believed that such a regimen could slow thedevelopment of resistance to the mutant KIT inhibitors.

Pharmaceutical Compositions

While it is possible for a compound disclosed herein to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation, where the compound is combined with one or morepharmaceutically acceptable excipients or carriers. The compoundsdisclosed herein may be formulated for administration in any convenientway for use in human or veterinary medicine. In certain embodiments, thecompound included in the pharmaceutical preparation may be activeitself, or may be a prodrug, e.g., capable of being converted to anactive compound in a physiological setting.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars,such as lactose, glucose and sucrose; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol®; and (22) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders,granules and the like) can include one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Ointments, pastes, creams and gels may contain, in addition to an activecompound, excipients, such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

When the compounds disclosed herein are administered as pharmaceuticals,to humans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with a pharmaceuticallyacceptable carrier.

The formulations can be administered topically, orally, transdermally,rectally, vaginally, parentally, intranasally, intrapulmonary,intraocularly, intravenously, intramuscularly, intraarterially,intrathecally, intracapsularly, intradermally, intraperitoneally,subcutaneously, subcuticularly, or by inhalation.

Dosages

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.0001 to about 100 mg perkilogram of body weight per day. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, sixor more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. In someembodiments, the dose for humans will be 100-400 mg, or 200-300 mg,administered twice daily; or 400-700 mg, or 500-600 mg, administeredonce daily.

EXAMPLES

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

The below Schemes are meant to provide general guidance in connectionwith preparing the compounds of the invention. One skilled in the artwould understand that the preparations shown in the Schemes can bemodified or optimized using general knowledge of organic chemistry toprepare various compounds of the invention.

Synthetic Protocol 1

The pyrrolotriazinone can be coupled (LG² can be, e.g., Cl, Br, or I) toa boron, tin or zinc aryl, heteroaryl, alkenyl, alkyl reagent via apalladium-mediated coupling reaction, e.g., Suzuki, Stille, Negishicoupling, to provide an intermediate with a new carbon-carbon bondformed after subsequent leaving group formation (via POCl₃ or othersimilar reagents). The resulting pyrrolotriazine can be substituted withan amine under nucleophilic aromatic substitution reaction conditionsusing a base such as diisopropylethylamine (DIPEA) or triethylamine(TEA) in a polar solvent such as dioxane to provide thepiperazine-substituted pyrrolotriazine. As shown below, Compounds 9, 10,and 107 were prepared using Synthetic Protocol 1.

Example 1 Synthesis of(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine and(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine(Compounds 9 and 10)

Step 1: Synthesis of (1-phenylethyl)zinc(II) bromide

To a suspension mixture of zinc powder (active, 5.1 g, 80.0 mmol) in dryTHF (20 mL) was added dropwise 1,2-dibromoethane (0.28 mL, 5.7 mmol) at70° C. under nitrogen atmosphere, followed by the addition ofchlorotrimethylsilane (1.2 mL, 10.6 mmol). Subsequently,(1-bromoethyl)benzene (3.7 g, 20 mmol) was added dropwise. The resultantsuspension was stirred at 70° C. for another 1 h. The reaction mixturewas cooled to RT and directly used for the next step.

Step 2: Synthesis of 5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine

To a solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (4.1 g, 12.0 mmol) andtetrakis(triphenylphosphine)palladium (708 mg, 1.0 mmol) in THF (80 mL,dry) was added dropwise a solution of (1-phenylethyl)zinc(II) bromide inTHF (20 mL, 1 M, 20 mmol) under nitrogen atmosphere, and the mixture wasstirred at 70° C. overnight. The reaction mixture was cooled to RT andfiltered through a pad of Celite. The filtration was concentrated andpurified by silica gel chromatography to give tert-butyl4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g,yield 23%) as a white solid (ethyl acetate/petroleum ether=1/5 as elute)and 5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (2.4 g, 75%) as ayellow oil (methanol/dichloromethane=1/20 as elute). MS (ES+) C₁₆H₂₀N₄requires: 268, found: 269 [M+H]⁺.

Step 3: Chiral separation of(R)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine and(S)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine

Racemate compound 5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (900mg) was separated by Chiral-HPLC under the below conditions:

Chiral column: AD-3 (150*4.6 mm 3 um)

Mobile phase hexane (0.1% DEA)/EtOH (0.1% DEA)

(R)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (400 mg, 44%) as ayellow oil and (S)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (350mg, 39%) as a yellow oil were obtained. Absolute stereochemistry wasassigned randomly. MS (ES+) C₁₆H₂₀N₄ requires: 268, found: 269 [M+H]⁺.Synthesis of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

Step 4: Synthesis of O-(diphenylphosphoryl)hydroxylamine

To a solution of hydroxylamine hydrochloride (7.3 g, 106 mmol, 2.5 eq)in water (12 mL) and dioxane (12 mL) was added a solution of NaOH (4.07g, 102 mmol, 2.4 eq) in water (12 mL), and the mixture was cooled to −5°C. in an ice/salt bath. A solution of diphenylphosphinic chloride (10 g,42 mmol, 1 eq) in dioxane (12 mL), precooled to below 10° C., wasrapidly added to the above solution in an ice/salt bath under vigorousstirring. After completion of the addition, the mixture was stirred foradditional 5 minutes in an ice/salt bath, then diluted with ice water(150 mL) and filtered. The filtration cake was washed with ice water,and lyophilized to give o-(diphenylphosphoryl)hydroxylamine (6.0 g,yield 61%) as a white solid. MS (ES+) requires: 233, found 234 [M+H];purity: 75%.

Step 5: Synthesis of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methylester

To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (3.5g, 17.2 mmol, 1 eq) in DMF (120 mL) was added NaH (0.82 g, 20.6 mmol,1.2 eq) at 0° C., and the mixture was stirred at 0° C. for 1 h, followedby the addition of o-(diphenylphosphinyl)-hydroxylamine (6 g, 25.8mmol). The reaction mixture was stirred for another 1 h, thenneutralized with 20% NH₄Cl solution, and extracted with EA. The combinedorganic layers were washed with water and brine, dried over sodiumsulfate, filtered, and concentrated by evaporation. The residue waspurified by column chromatography on silica gel (PE/EA=4:1) to give1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.9 g, yield77%) as a light yellow solid. MS (ES+) requires: 218, 220, found 219,221 [M+H]⁺; purity: 97%.

Step 6: Synthesis of 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one

A solution of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester(2.9 g, 13.2 mmol) in formamide (12 mL) was heated at 180° C. for 5 hrs.The mixture was diluted with ethyl acetate (300 mL), and then washedwith water (100 mL*2), brine (100 mL*3). The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting solid was washed with PE/EA (4:1, 50 mL) to give6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.4 g, yield 50%) asyellow solid.

MS (ES+) requires: 213, 215, found 214, 216 [M+H]⁺; purity: 92%.

Step 7: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl) pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

A mixture of 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.15 g, 10mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(4.2 g, 20 mmol), Cs₂CO₃ (9.8 g, 30 mmol), PdCl₂dppf (814 mg, 1 mmol),water (15 mL), ethanol (15 mL) and dioxane (70 mL) in a 250 mL flask wasdegassed with N₂ for 10 min, and then heated at 120° C. under N₂atmosphere overnight. The mixture was cooled to RT, followed by theaddition of silica gel (˜50 g). The residue was subjected to a silicagel column and eluted with DCM:MeOH (20:0-20:1) to afford6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-][1,2,4]triazin-4(3H)-one (600mg, 28% yield) as a yellow solid. MS (ES+) requires: 215, found 216.1[M+H]⁺; purity: 90%.

Step 8: Synthesis of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (600mg, 2.8 mmol) was treated with phosphorus oxychloride (20 mL) underreflux for 3 hours. The mixture was cooled to RT, concentrated underreduced pressure and the residue was diluted with ice water (100 mL).The mixture was extracted with dichloromethane (50 mL*4), and thecombined organic layers were dried by MgSO₄, filtered, concentrated togive 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine(600 mg, 92% yield) as a brown solid. MS (ES+) requires: 233, 235, found234, 236 [M+H]⁺; purity:90%.

Step 9: Synthesis of(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine

A mixture of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (56mg, 0.21 mmol), (R)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (49mg, 0.21 mmol) and diisopropylethylamine (97 mg, 0.84 mmol) in dioxane(10 mL) was stirred at RT overnight. LCMS monitored the reaction wascompleted. The reaction mixture was concentrated to give a residue,which was purified by Prep-HPLC to afford the title compound (45 mg,46%) as a white solid. MS (ES+) C₂₆H₂₇N₉ requires: 465 found: 466[M+H]⁺.

Step 10: Synthesis of(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine

A mixture of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (56mg, 0.21 mmol), (S)-5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (49mg, 0.21 mmol) and diisopropylethylamine (97 mg, 0.84 mmol) in dioxane(10 mL) was stirred at RT overnight. LCMS monitored the reaction wascompleted. The reaction mixture was concentrated to give a residue,which was purified by Prep-HPLC to afford the title compound (43 mg,44%) as a white solid. MS (ES+) C₂₆H₂₇N₉ requires: 465 found: 466[M+H]⁺.

Example 2: Synthesis of(S)-1-(2-(4-(5-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanol(Compound 107)

Step 1: Synthesis of methyl 3-chloro-1H-pyrrole-2-carboxylate

To a solution of 5-methyl-3,4-dihydro-2H-pyrrole (2.50 g, 30.0 mmol) inCCl₄ (100 mL) was added N-chlorosuccinimide (32.00 g, 240 mmol), and themixture was then heated to reflux for 72 hours. The reaction mixture wascooled to 0° C. The formed precipitate was filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in methanol (100 mL), followed by the addition of sodiummethoxide (9.80 g, 180 mmol). The resulting suspension was heated toreflux and stirred for 1.5 h. The solvent was evaporated, and theresidue was suspended in ether. The solid was filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in DCM (100 mL) and 2 M HCl (100 mL). The biphasic solutionwas stirred for 10 min. The organic layer was separated, dried overMgSO₄, filtered and evaporated. The crude oil was subjected tochromatography purification on silica gel eluting with EtOAc and Hexanesto afford the title compound (2.5 g, 52%) as an orange solid. MS (ES+)C₆H₆ClNO₂ requires: 159, found: 160 [M+H]⁺.

Step 2: Synthesis of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate

To a suspension of sodium hydride (60 percent, 1.5 g, 37.5 mmol) in DMF(250 mL) was added methyl 3-chloro-1H-pyrrole-2-carboxylate (5.0 g, 31.3mmol) at 0° C., and the mixture was stirred for 25 min, followed by theaddition of O-(diphenylphosphoryl)hydroxylamine (10.0 g, 43.75 mmol).The reaction mixture was stirred at RT for 4 h and quenched by aq.Na₂SO₃ solution. After stirred for another 5 min, the mixture wasextracted with EtOAc (3×300 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give crudeproduct as a brown oil, which was purified by chromatographypurification on silica gel (PE:EA=4:1) to obtain the title compound(5.00 g, 91%) as a white solid. MS (ES+) C₆H₇ClN₂O₂ requires: 174, 176,found: 175, 177 [M+H]⁺.

Step 3: Synthesis of 5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

A mixture of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (4.00 g,23 mmol) and formamide (15 mL) was heated to 180° C. for 3 h. Aftercooled to RT, the precipitated solid was collected via filtration andwashed with CH₂CH₂ to obtain the title compound (2.50 g, 64%) as ayellow solid. MS (ES+) C₆H₄ClN₃O requires: 169, found: 170 [M+H]⁺.

Step 4: Synthesis of6-bromo-5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

To a mixture of 5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2.50 g,14.7 mmol) in THF (100 mL) and MeOH (50 mL) was added N-bromosuccinimide(2.6 g, 14.7 mmol), and the mixture was stirred at RT for 2 h. Thereaction was quenched by water and extracted with EA. The organic layerwas dried (Na₂SO₄), filtered and concentrated. The residue was purifiedby chromatography purification on silica gel (EA:MeOH=10:1) to obtainthe title compound (2.00 g, 55%) as a yellow solid. MS (ES+) C₆H₃BrClN₃Orequires: 246.9, found: 247.9 [M+H]⁺.

Step 5: Synthesis of5-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

A mixture of 6-bromo-5-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one(2.00 g, 8.1 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.5 g, 12.1 mmol), K₃PO₄ (3.4 g, 16.1 mmol) and Pd(dppf)Cl₂ (589 mg,0.81 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was purged with N₂and then heated to 90° C. for 15 h. The reaction mixture was cooled toRT and concentrated. The residue was passed a column (silica gel,EA:DCM:MeOH=10:10:1) to obtain the title compound (600 mg, 30%) as ayellow solid. MS (ES+) C₁₀H₈ClN₅O requires: 249, 251, found: 250, 252[M+H]⁺.

Step 6: Synthesis of4,5-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

A mixture of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(600 mg, 2.4 mmol) in POCl₃ (4 mL) was heated to reflux for 12 h. Thereaction mixture was cooled to RT and concentrated under reducedpressure. The residue was washed with a mixture of THF (20 mL) and1,4-dioxane (10 mL) to give the title compound (450 mg, 69%) as a yellowsolid. MS (ES+) C₁₀H₈ClN₅O requires: 267, 269, found: 268, 270 [M+H]⁺.

Step 7: Synthesis of(S)-1-(2-(4-(5-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanol

To a mixture of4,5-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine(150 mg, 0.56 mmol) and(S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol (135mg, 0.45 mmol) in 1,4-dioxane (10 mL) was added DIPEA (361 mg, 2.8mmol). After stirred at RT for 15 h, the mixture was concentrated underreduced pressure and purified by Prep-HPLC to give the title compound(40.9 mg, 17%) as a white solid. MS (ES+) C₂₆H₂₅ClFN₉O requires: 533,found: 534 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d4) δ ppm 8.41 (s, 1H), 8.39(s, 2H), 8.13 (s, 1H), 8.09 (s, 1H), 7.48-7.44 (m, 2H), 7.22 (s, 1H),7.14-7.10 (m, 2H), 5.91 (s, 1H), 3.95-3.89 (m, 7H), 3.71-3.68 (m, 4H),1.82 (s, 3H).

Synthetic Protocol 2

The pyrrolotriazinone can be transformed into a pyrrolotriazine viatreatment with POCl₃ or other similar reagents. The pyrrolotriazine canbe substituted with an amine under nucleophilic aromatic substitutionreaction conditions using an amine base such as diisopropylethylamine(DIPEA) or triethylamine (TEA) in a polar solvent such as dioxane toprovide the piperazine-substituted pyrrolotriazine. Thepyrrolotriazinone can be coupled (LG² can be, e.g., Cl, Br, or I) to aboron, tin or zinc aryl, heteroaryl, alkenyl, or alkyl reagent via apalladium-mediated coupling reaction, e.g., Suzuki, Stille, Negishicoupling, to provide the product. As shown below, Compound 123 wasprepared using Synthetic Protocol 2.

Example 3: Synthesis of(S)-2-((4-(4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine(Compound 123)

Step 1: Synthesis of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate

To a mixture of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate(400 mg, 1.84 mmol) in 10 mL of dichloromethane was added triethylamine(372 mg, 3.68 mmol) and methanesulfonyl chloride (316 mg, 2.76 mmol)dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3 h, andLCMS showed the reaction was completed. The reaction solution wasdiluted with 20 mL of dichloromethane, and washed with saturated aqueousNaHCO₃ (30 mL×3) and brine. The organic layer was separated, dried oversodium sulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography (petroleum ether:ethylacetate=5:1) to afford the title product (430 mg, 79%) as a white solid.MS (ES+) C₁₁H₂₁NO₆S requires: 295, found: 296 [M+H]⁺.

Step 2: Synthesis of (S)-tert-butyl2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a mixture of (S)-tert-butyl2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (430 mg, 1.46mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(283 mg, 1.46 mmol) in 50 mL of acetonitrile was added cerium carbonate(1.43 g, 4.37 mmol), and the mixture was stirred at 60° C. for 3 h. TLCand LCMS showed the reaction was completed. After the solvents wereremoved under reduced pressure, the residue was diluted with 50 mL ofethyl acetate, and washed with water (50 mL×3) and brine. The organiclayer was separated, dried over sodium sulfate, filtered andconcentrated. The crude product was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1) to get the titleproduct (300 mg, 52%) as colorless oil. MS (ES+) C₁₉H₃₂BN₃O₅ requires:393, found: 394 [M+H]⁺.

Step 3: Synthesis of tert-butyl4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol),2-fluorobenzenethiol (9.3 g, 73 mmol), 1,10-Phenanthroline (7.9 g, 43.8mmol), copper iodide (13.9 g, 73 mmol) and cerium carbonate (28.6 g,87.6 mmol) in dioxane (100 mL) was refluxed for 3 days. The reactionmixture was cooled to RT and concentrated. The residue was directlypurified by silica gel chromatography to give the title compound. MS(ES+) C₁₉H₂₃FN₄O₂S requires: 390, found: 391 [M+H]⁺.

Step 4: Synthesis of 5-(2-fluorophenylthio)-2-(piperazin-1-yl)pyrimidineHCl salt

To a solution of tert-butyl4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazine-1-carboxylate (5 g,12.8 mmol) in dioxane (150 mL) was added HCl in dioxane (4 M, ca. 30mL), and the mixture was stirred at 40° C. overnight. LCMS showed thereaction was completed. The reaction mixture was concentrated to afford5-(2-fluorophenylthio)-2-(piperazin-1-yl)pyrimidine HCl salt (3.6 g,88%) as a solid. MS (ES+) C₁₄H₁₅FN₄S requires: 290, found: 291 [M+H]⁺.

Step 5: Synthesis of 6-bromo-4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine

A mixture of 6-bromo-4-chloropyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.43mmol), 5-(2-fluorophenylthio)-2-(piperazin-1-yl)pyrimidine HCl salt (126mg, 0.43 mmol) and diisopropylethylamine (280 mg, 2.15 mmol) in dioxane(5 mL) was stirred at RT overnight. The reaction mixture wasconcentrated and purified by silica gel chromatography (petroleumether:ethyl acetate=2:1) to afford the title compound as (100 mg, 49%) ayellow solid. MS (ES+) C₂₀H₁₇BrFN₇S requires: 485, 487, found: 486, 488[M+H]⁺.

Step 6: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

A mixture of 6-bromo-4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazine (100 mg, 0.2 mmol),(S)-tert-butyl2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(80 mg, 0.2 mmol), Pd₂(dba)₃ (34 mg, 0.02 mmol), Brettphos (40 mg, 0.04mmol) and cerium carbonate (260 mg, 0.4 mmol) in dioxane (5 mL) wasdegassed with nitrogen for three times, and then heated at 120° C.overnight. The reaction mixture was cooled to RT and concentrated togive a residue, which was purified by silica gel chromatography(dichloromethane:methanol=15:1) to afford the title compound (40 mg,30%) as a white solid. MS (ES+) C₃₃H₃₇FN₁₀O₃S requires: 672, found: 617[M−56+H]⁺.

Step 7: Synthesisof(S)-2-((4-(4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine

A mixture of (S)-tert-butyl2-((4-(4-(4-(5-(2-fluorophenylthio)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(40 mg, 0.06 mmol) in HCl/dioxane (5 mL) was stirred at RT for 2 h. Thereaction mixture was concentrated to give a residue, which was purifiedby Prep-HPLC to afford the title compound (8.9 mg, 26%) as a yellowsolid. MS (ES+) C₂₈H₂₉FN₁₀OS requires: 572, found: 573 [M+H]⁺.

Synthetic Protocol 3

The piperazine carbonyl derivative, e.g., carbamoyl, (A, X and Y areeach —CH—) can be coupled to the Grignard bromide (B, Ring A is aryl),to provide the protected di-substituted carbonyl (C, X is CH₂, S, NH, orO). When X¹ is O, i.e., forming a carbonyl, the carbonyl can be furtherreacted with an organometallic reagent such as Grignard, lithium, zincreagents and trialkylaluminum, e.g., trimethylaluminum, which can alsodeprotect the piperazine nitrogen to provide the further substitutedcompound (C′). Removal of the protecting group (P) from the piperazinering of (C) can be carried out using strong acids such as 4Mhydrochloric acid (HCl) in dioxane or trifluoroacetic acid (TFA) in apolar solvent such as methanol or dichloromethane (DCM) to afford amine(D). Pyrrolotriazine (E) can be substituted with amine (C′) or (D) undernucleophilic aromatic substitution reaction conditions using an aminebase such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in apolar solvent such as dioxane to provide the piperazine-substitutedpyrrolotriazine (F) or (F′). Reduction of —C(═X¹)—, wherein X¹ is CH₂,S, NH, or O, e.g., carbonyl, of (F) can be performed using a reducingagent such as sodium borohydride to provide —C—(XH)—, e.g., the alcohol(G). Alternatively, alkylation of X² can be performed using alkylhalides (alternative leaving groups) to provide X³-containing analogs(G′). Enantiomeric enriched products can be obtained via catalyticasymmetric synthesis, chiral auxiliary based synthesis and resolution ofa racemate. As shown below, Compounds 40 and 41 were prepared usingSynthetic Protocol 3.

Example 4: Synthesis of4-(4-(5-(1-(4-fluorophenyl)propyl)pyrimidin-2-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine(Compounds 40 and 41)

Step 1: Synthesis of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol)and diisopropylethylamine (23.4 mL, 134.25 mmol) in dioxane (80 mL) wasadded ethyl 2-chloropyrimidine-5-carboxylate (10 g, 53.7 mmoL), and thereaction mixture was stirred at RT for 3 h. LCMS showed the reaction wascompleted. The reaction was concentrated to afford the title compound(17 g, crude), which was directly used in the next step without thefurther purification. MS (ES+) C₁₆H₂₄N₄O₄ requires: 336, found: 237, 281[M−56+H]⁺.

Step 2: Synthesis of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid

To a solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g,crude) in THF/MeOH/water (300 mL) was added sodium hydroxide (4.3 g,107.5 mmol), and the reaction was stirred at 70° C. for 2 h. LCMS showedthe reaction was completed. The reaction mixture was cooled to RT,acidified to pH ˜ 5-6 with 1 M HCl and filtered. The solid was collectedand dried to give the title compound (16 g, 96%) as a white solid, whichwas directly used in the next step without further purification. MS(ES+) C₁₄H₂₀N₄O₄ requires: 308, found: 253 [M−56+H]⁺.

Step 3: Synthesis of tert-butyl4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a suspension of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid(13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2mmol), and the mixture was stirred at RT for 1 h, followed by theaddition of N,O-dimethylhydroxylamine (5 g, 53.7 mmol). The reaction wasstirred for another 3 h. LCMS showed the reaction was completed. Thereaction mixture was washed with water (100 mL), and the organic layerwas dried, filtered and concentrated. The residue was purified by silicagel chromatography (petroleum ether:ethyl acetate=1:1) to give the titlecompound (11.2 g, 67%) as a white solid. MS (ES+) C₁₆H₂₅N₅O₄ requires:351, found: 296 [M−56+H]⁺.

Step 4: Synthesis of tert-butyl4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate(7.8 g, 22.22 mmol) in dry THF (50 mL) was added C₆H₅MgFBr (1 M in THF,50 mL) at 0° C. under nitrogen, and the mixture was stirred at RT for 3h. LCMS showed the reaction was completed. The reaction was quenchedwith 1 M HCl and extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over sodium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound (7.2 g, 84%) as a yellow solid. MS (ES+) C₂₀H₂₃FN₄O₃ requires:386, found: 331 [M−56+H]⁺.

Step 5: Synthesis of(4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone

To a solution of tert-butyl4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (8.2 g,21.24 mmol) in dioxane (50 mL) was added HCl in dioxane (4 M, 20 mL).The reaction mixture was stirred at RT overnight. LCMS showed thereaction was completed. The mixture was concentrated to get the titlecompound as a light yellow solid (5.5 g, 90%). MS (ES+) C₁₅H₁₅FN₄Orequires: 286, found: 287 [M+H]⁺.

Step 6: Synthesis of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol

To a solution of(4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (4.0 g,21.84 mmol) in dry THF (150 mL) was added EtMgBr (1 M in THF, 150 mL) at0° C. under nitrogen. The mixture was stirred at RT for 3 h, thenquenched with NH₄Cl solution and extracted with ethyl acetate (200*3mL). The combined organic layers were washed with water and brine, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby combi-flash with dichloromethane:methanol=10:1 to give the titlecompound (440 mg, 10%) as a yellow solid. MS (ES+) C₁₇H₂₁FN₄O requires:316, found: 317 [M+H]⁺.

Step 7: Synthesis of(E)-5-(1-(4-fluorophenyl)prop-1-enyl)-2-(piperazin-1-yl)pyrimidine

To a solution of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol (200mg, 0.6 mmol) in dioxane (10 mL) was added HCl in dioxane (4 M, 10 mL),and the reaction was stirred at RT for 1 h. LCMS showed the reaction wascompleted. The mixture was concentrated to an oil, which was purified byCombiflash with dichloromethane:methanol=20:1 to give the title compoundas a light yellow solid (185 mg, 98%). MS (ES+) C₁₇H₁₉FN₄ requires: 298,found: 299 [M+H]⁺.

Step 8: Synthesis of5-(1-(4-fluorophenyl)propyl)-2-(piperazin-1-yl)pyrimidine

To a solution of(E)-5-(1-(4-fluorophenyl)prop-1-enyl)-2-(piperazin-1-yl)pyrimidine (170mg, 0.57 mmol) in methanol (10 mL) was added Pd/C (30 mg). The mixturewas exposed to 1 atm hydrogen (balloon) and stirred at RT for 1 h. Themixture was filtrated, and the filtrate was concentrated to an oil,which was purified by combiflash with dichloromethane:methanol=50:1 togive the title compound (racemate, 90 mg, 53%) as a yellow oil.

Step 9: Chiral separation of(R)-5-(1-(4-fluorophenyl)propyl)-2-(piperazin-1-yl)pyrimidine and(S)-5-(1-(4-fluorophenyl)propyl)-2-(piperazin-1-yl)pyrimidine

The above racemate compound (90 mg) was separated by Chiral-HPLC toafford the enantiomers (35 mg). MS (ES+) C₁₇H₂₁FN₄ requires: 300, found:301 [M+H]⁺. The absolute stereochemistry was assigned randomly.

Chiral separation condition: Chiral column: OJ-H (250*4.6 mm 5 um)

Mobile phase: n-Hexane (0.1% DEA):EtOH (0.1% DEA)=95:5

Step 10a: Synthesis of(R)-4-(4-(5-(1-(4-fluorophenyl)propyl)pyrimidin-2-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

A solution of(R)-5-(1-(4-fluorophenyl)propyl)-2-(piperazin-1-yl)pyrimidine 36 mg,0.12 mmol),4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (31mg, 0.132 mmol) and diisopropylethylamine (47 mg, 0.36 mmol) in1,4-dioxane (5 mL) was stirred at RT for 3 h. The reaction mixture wasconcentrated, and the residue was purified by Prep-HPLC to give thetitle compound (21.1 mg, 35%) as a white solid. MS (ES+) C₂₆H₂₆FN₉Orequires: 497, found: 498 [M+H]⁺.

Step 10b: Synthesis of(S)-4-(4-(5-(1-(4-fluorophenyl)propyl)pyrimidin-2-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

A mixture of(S)-5-(1-(4-fluorophenyl)propyl)-2-(piperazin-1-yl)pyrimidine 35 mg,0.12 mmol),4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (30mg, 0.132 mmol) and diisopropylethylamine (47 mg, 0.36 mmol) in1,4-dioxane (5 mL) was stirred at RT for 3 h. The reaction mixture wasconcentrated, and the residue was purified by Prep-HPLC to give thetitle compound (24.4 mg, 35%) as a white solid. MS (ES+) C₂₆H₂₆FN₉Orequires: 497, found: 498 [M+H]⁺.

Synthetic Protocol 4

The piperazine shown above can be prepared using similar syntheticprocedures shown in Synthetic Protocol 3. The pyrrolotriazine can besubstituted with the amine of the piperazine under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted pyrrolotriazine.Direct condensation of chiral tert-butanesulfinamide with the ketone ofthe piperazine-substituted pyrrolotriazine can provide the chiralN-sulfinyl imine. 1,2-addition of a nucleophile, such as anorganometallic reagent, e.g., an alkyl Grignard, or, e.g., an enolate,to the N-sulfinyl imine, followed by cleavage of the N-sulfinyl groupunder, e.g., acidic conditions, can provide the chirally enriched amine.Chirally pure amine can be obtained by chiral chromatography, e.g., SFCor HPLC. The compounds prepared by Synthetic Protocol 4 were separatedby chiral SFC using the following separation conditions:

-   -   Column: ChiralPak AS-H 20×250 mm    -   Mobile Phase: 45% ethanol containing 0.25% DEA in CO₂    -   Flow rate: 70 ml/min    -   Sample: 93.7 mg racemic mixture was dissolved in 15 ml solvent        consisting of methanol/ethanol=1/1 containing 150 uL        diethylamine    -   Injection: 2 mL per run    -   Detection: 254 nm

As shown below, Compounds 12, 13, 36, 43 and 44 were prepared usingSynthetic Protocol 4.

Example 5: Synthesis of(S)-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamineand(R)-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(Compounds 12 and 13)

Step 1: Synthesis of(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanimine

(S,Z)-2-Methyl-N-((2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methylene)propane-2-sulfinamide(490 mg, 0.862 mmol) was stirred in 4 M HCl in 1,4-dioxane (2 mL)/MeOH(2 mL) at room temperature for 1 hour. The solvent was removed in vacuoand the residue triturated in EtOAc to give(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanimine,HCl (490 mg, 0.861 mmol, 100% yield) as a pale yellow solid, 88% byweight.

MS (ES+) C₂₅H₂₄N₁₀ requires: 464, found: 465 [M+H]⁺.

Step 2: Synthesis ofrac-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine

(2-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanimine,HCl (410 mg, 0.818 mmol) was suspended in MeOH (8 mL). Sodiumborohydride (40 mg, 1.057 mmol) was added in one portion, producing anexotherm and forming a clear solution. Additional sodium borohydride (40mg, 1.057 mmol) was added in one portion, producing an exotherm andforming a suspension. The MeOH was removed in vacuo and the residuepartitioned between EtOAc-NaHCO₃. The aqueous phase was extracted asecond time with EtOAc. The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was recrystallized from EtOH to give(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(182 mg, 0.390 mmol, 47.7% yield) as an off-white solid.

MS (ES+) C₂₅H₂₆N₁₀ requires: 466, found: 467 [M+H]⁺.

Step 3: Separation of Enantiomers

The enantiomers of racemic(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(185 mg, 0.397 mmol) were separated by chiral SFC to give(S)-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(74 mg, 0.159 mmol, 80.0% yield) and(R)-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(94 mg, 0.201 mmol, 100% yield). The absolute stereochemistry wasassigned randomly.

MS (ES+) C₂₅H₂₆N₁₀ requires: 466, found: 467 [M+H]⁺.

Example 6: Synthesis of(S)—N,N-dimethyl-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-phenylmethanamine(Compound 36)

(S)-(2-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanamine(72 mg, 0.154 mmol) and formaldehyde (125 mg, 1.543 mmol) were taken upin MeCN (1.5 mL). Sodium cyanoborohydride (25 mg, 0.398 mmol) was added,followed by acetic acid (0.02 mL, 0.349 mmol) and the resulting mixturewas stirred at room temperature for 3 hours. Saturated NaHCO₃ was addedand the products extracted into DCM (×2). The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification of the residue by MPLC (0-10% MeOH-DCM), followed byMPLC (0-10% MeOH-EtOAc), followed by MPLC (0-8% MeOH-EtOAc) gave(S)—N,N-dimethyl-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-phenylmethanamine(15 mg, 0.030 mmol, 19.65% yield).

MS (ES+) C₂₇H₃₀N₁₀ requires: 494, found: 495 [M+H]⁺.

Example 7: Synthesis of(R)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamineand(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine(Compounds 43 and 44)

Step 1: Synthesis of(4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methanone

4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (180mg, 0.770 mmol),(4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone, HCl (265mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammoniumchloride was added and the products extracted into DCM (×2). Thecombined organic extracts were dried over Na₂SO₄, filtered throughCelite eluting with DCM, and the filtrate concentrated in vacuo.Purification of the residue by MPLC (25-100% EtOAc-DCM) gave(4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methanone(160 mg, 0.331 mmol, 43% yield) as an off-white solid. MS (ES+)C₂₅H₂₂FN₉O requires: 483, found: 484 [M+H]⁺.

Step 2: Synthesis of(S,Z)—N-((4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol),(4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methanone(158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) werestirred in THF (3.2 mL) at 70° C. for 18 hours. Room temperature wasattained, water was added, and the products extracted into EtOAc (×2).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo while loading onto Celite.Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave(S,Z)—N-((4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide(192 mg, 0.327 mmol, 100% yield) as an orange solid. MS (ES+)C₂₉H₃₁FN₁₀OS requires: 586, found: 587 [M+H]⁺.

Step 3: Synthesis of(S)—N-(1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide

(S,Z)—N-((4-Fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide(190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0° C.Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500mmol) was added and the resulting mixture stirred at 0° C. for 45minutes. Additional methylmagnesium bromide (3 M solution in diethylether, 0.10 mL, 0.300 mmol) was added and stirring at 0° C. continuedfor 20 minutes. Saturated ammonium chloride was added and the productsextracted into EtOAc (×2). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo whileloading onto Celite. Purification of the residue by MPLC (0-10%MeOH-EtOAc) gave(S)—N-(1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide(120 mg, 0.199 mmol, 61.5% yield) as a yellow solid (mixture ofdiastereoisomers). MS (ES+) C₃₀H₃₅FN₁₀OS requires: 602, found: 603[M+H]⁺.

Step 4: Synthesis of1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine

(S)—N-(1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide(120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH(1.5 mL) at room temperature for 1 hour. The solvent was removed invacuo and the residue triturated in EtOAc to give1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine,HCl (110 mg, 0.206 mmol, 103% yield) as a pale yellow solid. MS (ES+)C₂₆H₂₇FN₁₀ requires: 498, found: 482 [M−17+H]⁺, 499 [M+H]⁺.

Step 5: Chiral separation of(R)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamineand(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine

The enantiomers of racemic1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine(94 mg, 0.189 mmol) were separated by chiral SFC to give(R)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine(34.4 mg, 0.069 mmol, 73.2% yield) and(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine(32.1 mg, 0.064 mmol, 68.3% yield). The absolute stereochemistry wasassigned randomly. MS (ES+) C₂₆H₂₇FN₁₀ requires: 498, found: 499 [M+H]⁺.

Preparation of Common Intermediates Synthesis of5-(2-phenylpropan-2-yl)-2-(piperazin-1-yl)pyrimidine

In a sealed tube, the mixture of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (500 mg, 1.36 mmol) and trimethylaluminum (2 Min toluene, 2.7 mL) in dry toluene (10 mL) was stirred at 100 0° C.overnight. LCMS showed the reaction was completed. The reaction mixturewas cooled to RT, quenched with ice-water and extracted with ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated. The residue was purified byPrep-HPLC to get 5-(2-phenylpropan-2-yl)-2-(piperazin-1-yl)pyrimidine(40 mg, 7%) as a yellowish solid. MS (ES+) C₁₇H₂₂N₄ requires: 282,found: 283 [M+H]⁺.

Synthesis of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixturewas stirred under reflux for 1.5 h. The reaction was cooled to RT,quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2).The combined organic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified with silica gel chromatography(petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5g, 80%) as a white solid. MS (ES+) C₁₃H₁₉BrN₄O₂ requires: 342, found:243 [M+H−100]⁺.

Synthesis of tert-butyl4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol),palladium diacetate (240 mg, 1.46 mmol), triphenylphosphine (376 mg,2.92 mmol) and tributyl(1-ethoxyvinyl)stannane (5.3 mL, 16.1 mL) indioxane (100 mL) was degassed with nitrogen for three times, and thereaction mixture was stirred at 80° C. overnight. The reaction wascooled to RT and diluted with THF (100 mL), followed by the addition of2 N HCl (100 mL). The mixture was stirred at RT for 30 mins, and LCMSshowed the reaction was completed. The reaction mixture was diluted withethyl acetate (200 mL). The organic phase was separated, washed withwater (3×100 mL), dried over sodium sulfate, filtered and concentrated.The residue was purified by silica gel chromatography to afford thetitle compound (3.0 g, 67%). MS (ES+) C₁₅H₂₂N₄O₃ requires: 306, found:251 [M−56+H]⁺.

Synthesis of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone

To a solution of tert-butyl4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (3 g, 9.8 mmol) indichloromethane (30 mL) was added trifluoroethyl acetate (15 mL), andthe mixture was stirred at RT for 30 min. LCMS showed the reaction wascompleted. The reaction mixture was neutralized with sodium carbonatesolution and extracted with dichloromethane. The organic layer was driedover sodium sulfate, filtered and concentrated to afford the titlecompound as a light yellow solid (2 g, 100%), which was directly used inthe next step without further purification. MS (ES+) C₁₀H₁₄N₄O requires:206, found: 207 [M+H]⁺.

Synthesis of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

To a solution of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone (1.8 g,8.73 mmol) in dry THF (100 mL) was added (4-fluorophenyl)magnesiumbromide (1 M in THF, 87.3 mL) at 0° C. under N₂. The mixture was stirredat RT for 3 h, then quenched with ammonium chloride solution andextracted with dichloromethane (300 mL). The organic layer was driedover sodium sulfate, filtered and concentrated. The residue was purifiedby Combi-flash (dicholomethane:methanol=10:1) to give the title compound(1.02 g, 38%) as a yellow solid.

Chiral separation of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

The racemate compound (1.02 g) was separated by chiral HPLC to affordenantiomer 1 (E1, 320 mg) and enantiomer 2 (E2, 220 mg). MS (ES+)C₁₆H₁₉FN₄O requires: 302, found: 303 [M+H]⁺. The absolute configurationwas assigned randomly.

Chiral separation conditions: Chiral column: OZ-H (4.6*250 mm, 5 um);Mobile phase: co-solvent EtOH (0.1% DEA)

Synthesis of(S)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol and(R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

Step 1: Synthesis of 4-fluoro-N-methoxy-N-methylbenzamide

To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol),N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine(553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight.The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4),water (1 L) and brine (1 L) sequentially. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo to give the titlecompound (150 g, yield 57%). MS (ES+) C₉H₁₀FNO₂ requires: 183, found 184[M+H]⁺; purity: 90% (UV254).

Step 2: Synthesis of tert-butyl4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (50 g, 146.2 mmol) inanhydrous THF (700 mL) was dropwise added n-BuLi (2.5 M in hexane, 70mL, 175 mmol) at −78° C. under nitrogen. The mixture was stirred at −78°C. for 1 h, followed by the addition of a solution of4-fluoro-N-methoxy-N-methylbenzamide (30 g, 163.9 mmol) in anhydrous THF(100 mL). After stirred at −78° C. for another 2 h, the reaction mixturewas quenched with saturated aqueous NH₄Cl (250 mL) and extracted withethyl acetate (200 mL*3). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo. The residue wasdiluted with propan-2-ol (150 mL) and stirred at RT for 30 mins. Thesolid was collected via filtration, washed with propan-2-ol (100 mL) andpetroleum ether (300 mL), and dried under vacuum to give the titlecompound (26 g, yield 46%) as a yellow solid. MS (ES+) C₂₀H₂₃FN₄O₃requires: 386, found 331 [M−56+H]⁺; purity: 100% (UV214).

Step 3: Synthesis of tert-butyl4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl) iperazine-1-carboxylate

To a solution of methyltriphenylphosphonium bromide (6.0 g, 16.84 mmol)in THF (40 mL) at −78° C. was dropwise added n-BuLi (2.4 M, 7.2 mL,17.19 mmol). After stirred at −78° C. for 1 h, tert-butyl4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.3 g,3.37 mmol) was added. The reaction mixture was stirred at RT overnight.LCMS showed the reaction was completed. The reaction was quenched withaqueous NH₄Cl solution and extracted with EA (2×50 mL). The organicphases were washed with H₂O (3×30 mL) and brine (50 mL), dried oversodium sulfate, filtered, concentrated and purified by silica gelchromatography (PE:EA=10:1) to get the title compound as a white solid(1.2 g, 93%). MS (ES+) C₂₁H₂₅FN₄O₂ requires: 384, found: 329 [M−56+1]⁺.

Step 4: Synthesis of tert-butyl4-(5-(1-(4-fluorophenyl)-2-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carboxylat

Tert-butyl4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl)piperazine-1-carboxylate(1.2 g, 3.12 mmol) was dissolved in THF (30 mL) and then cooled to 0°C., followed by the addition of BH₃.THF (6.24 mL, 6.24 mmol) dropwise.The mixture was stirred at RT for 3 h. To the mixture was added H₂O inTHF (10%, 8 mL), a solution of NaOH (1.25 g) in 30 mL H₂O and H₂O₂(35%,18 g) sequentially at 0° C. The mixture was stirred at RT overnight. Themixture was acidified with 1 N HCl and extracted with EA (3×50 mL). Theorganic phases were washed with aqueous NaHCO₃ (50 mL), brine (50 mL),dried over sodium sulfate, filtered, concentrated and purified by silicagel chromatography (DCM:CH₃OH=30:1) to get the title compound as a whitesolid (0.3 g, 24%). MS (ES+) C₂₁H₂₇FN₄O₃ requires: 402, found: 403[M+H]⁺.

Step 5: Synthesis of2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

To a solution of tert-butyl4-(5-(1-(4-fluorophenyl)-2-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carboxylat(450 mg, 1.08 mmol) in dioxane (5 mL) was added HCl/dioxane (5 mL). Themixture was stirred at RT overnight. LCMS showed the reaction wascompleted. The solution was concentrated and purified by silica gelchromatography (DCM:CH₃OH=10:1) to get the title compound as a yellowsolid (0.2 g, 53%). MS (ES+) C₁₆H₁₉FN₄O requires: 302, found: 303[M+H]⁺.

The above sample (200 mg, 0.66 mmol) was separated by Chiral-HPLC to get(S)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanolassumed (1^(st) peak, 50 mg, 25%) and(R)-2-phenyl-2-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol assumed (2^(nd)peak, 50 mg, 25%).

Synthesis of tert-butyl4-(5-(4-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol),4-fluorophenol (1.1 g, 5.0 mmol), copper (650 mg, 10.0 mmol) and Cs₂CO₃(6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120° C. for 12 h.The mixture was cooled to RT, diluted with ethyl acetate (200 mL) andfiltered. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (petroleumether/ethyl acetate=20/1) to afford the title compound (200 mg, 27%) asa brown solid. MS (ES+) C₁₉H₂₃FN₄O₃ requires: 374, found: 319 [M−56+1]⁺.

Synthesis of 5-(4-fluorophenylsulfonyl)-2-(piperazin-1-yl)pyrimidine HClsalt

Step 1: Synthesis of tert-butyl4-(5-(4-fluorophenylthio)pyrimidin-2-yl)piperazine-1-carboxylate

A stirred solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.924 mmol),4-fluorobenzenethiol (561 mg, 4.386 mmol), Pd₂(dba)₃ (267 mg, 0.292mmol), Xantphos (169 mg, 0.292 mmol) and DIPEA (754 mg, 5.848 mmol) indioxane (50 mL) was degassed with nitrogen for three times, and thenheated at 110° C. for 16 hrs. The reaction mixture was cooled to RT andconcentrated under reduced pressure to give a residue, which waspurified by flash chromatography (silica gel, 0-20% EtOAc/PE) to affordthe title compound as a white solid. (500 mg, yield 44%, purity: 99%).MS (ES+) C₁₉H₂₃FN₄O₂S requires: 390, found 391 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(5-(4-fluorophenylsulfonyl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(5-(4-fluorophenylthio)pyrimidin-2-yl)piperazine-1-carboxylate (700mg, 1.799 mmol) and mCPBA (619 mg, 3.599 mmol) in DCM (20 mL) wasstirred at RT for 16 hrs. The reaction mixture was washed sequentiallywith saturated potassium carbonate solution, water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography (silica gel, 0-20% EtOAc/PE) to afford the title compoundas a white solid. (600 mg, yield 83%, purity: 100%). MS (ES+)C₁₉H₂₃FN₄O₄S requires: 422, found 423 [M+H]⁺.

Step 3: Synthesis of5-(4-fluorophenylsulfonyl)-2-(piperazin-1-yl)pyrimidine HCl salt

To a solution of tert-butyl4-(5-(4-fluorophenylsulfonyl)pyrimidin-2-yl)piperazine-1-carboxylate(100 mg, 0.237 mmol) in dioxane was added 4 M HCl/dioxane (6 mL). Themixture was stirred at RT for 3 hrs and concentrated to afford the titlecompound as a yellow oil, which was used into the next step withoutfurther purification. MS (ES+) C₄H₁₅FN₄O₂S requires: 322, found 323[M+H]⁺.

Synthesis of(R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-oland(S)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol

Step 1: Synthesis of tert-butyl4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of dicyclohexylamine (3.43 g, 18.94 mmol) in THF (60 mL)at −78° C. was added n-BuLi (2.5 M, 7.9 mL, 18.94 mmol) dropwise. Themixture was stirred at RT for 10 min, followed by the addition of methyl2-(4-fluorophenyl)acetate (2.69 g, 16.02 mmol) in toluene (60 mL). Afterstirred at RT for another 10 min, tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.57 mmol),Pd₂(dba)₃ (667 mg, 0.728 mmol) and P(t-Bu)₃ (10%, 1.47 g, 0.728 mmol)were added sequentially. The reaction mixture was stirred at RT for 15h, quenched by water (150 mL) and extracted with EA. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated. The residue was passed a column (silica gel,PE:EA=6:1) to afford the title compound (0.5 g, 8%) as an orange solid.MS (ES+) C₂₂H₂₇FN₄O₄ requires: 430, found: 431 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(5-(2-(4-fluorophenyl)-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate(1.0 g, 2.33 mmol) in THF (20 mL) at −78° C. was added LDA (2 M, 2.33mL, 4.65 mmol) dropwise, After stirred at −78° C. for 30 min, CH₃I (0.66g, 4.65 mmol) was added. After stirred at RT for another 1 h, thereaction was quenched by water and extracted with EA. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated. The residue was passed a column (silica gel,PE:EA=6:1) to afford the title compound (0.8 g, 77%) as a yellow solid.MS (ES+) C₂₃H₂₉FN₄O₄ requires: 444, found: 445 [M+H]⁺.

Step 3: Synthesis of tert-butyl4-(5-(2-(4-fluorophenyl)-1-hydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(5-(2-(4-fluorophenyl)-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate(0.4 g, 0.9 mmol) in THF (10 mL) was added LiBH₄ (40 mg, 1.8 mmol).After stirred at RT for 2 h, the reaction was quenched by aq. NH₄Cl andextracted with EA. The combined organic layers were washed with waterand brine, dried over Na₂SO₄, filtered and concentrated. The residue waspassed a column (silica gel, PE:EA=1:1) to afford the title compound(225 mg, 60%) as a yellow solid. MS (ES+) C₂₂H₂₉FN₄O₃ requires: 416,found: 417 [M+H]⁺.

Step 4: Synthesis of(R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol

To a mixture of tert-butyl4-(5-(2-(4-fluorophenyl)-1-hydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate(450 mg, 1.08 mmol) in DCM (20 mL) was added 4 M HCl/1,4-dioxane (3 mL).After stirred at RT for 15 h, the reaction mixture was concentrated, theresidue was diluted by aq. NaHCO₃ (20 mL) and extracted with DCM. Thecombined organic layers were washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The residue was separated by chiralPrep-HPLC to give(R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol(100 mg, 29%) as a white solid. MS (ES+) C₁₇H₂₁FN₄O requires: 316,found: 317 [M+H]⁺. Chiral HPLC, Column: IC 4.6*150 mm 5 um,Co-Solvent:EtOH:Hexane=1:1 (0.1% DEA), RT=4.22 min.

(S)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol(100 mg, 29%) as a white solid.

MS (ES+) C₁₇H₂₁FN₄O requires: 316, found: 317 [M+H]⁺. Chiral HPLC,Column: IC 4.6*150 mm 5 um, Co-Solvent: EtOH:Hexane=1:1(0.1% DEA),RT=5.43 min.

Synthesis of5-(3-(4-fluorophenyl)oxetan-3-yl)-2-(piperazin-1-yl)pyrimidine

Step 1: Synthesis of tert-butyl4-(5-(2-(4-fluorophenyl)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate(650 mg, 1.5 mmol) in THF (20 mL, dry) was cooled to −78° C. andprotected with N₂. Another solution of n-BuLi (1.5 M, 3 mL, −4.5 mmol)in THF was added to the above cooled solution during 5 min. The reactionmixture was stirred at −78° C. for 1 h, followed by the addition ofparaformaldehyde (405 mg, 15.0 mmol) in one portion under −78° C. Thissolution was stirred at RT overnight. The reaction was quenched bysaturated aqueous NH₄Cl (50 mL) and water (50 mL), and extracted withEtOAc (50 mL*4). The combined organic layer were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column eluting with PE:EA (4:1) toobtain the title compound as a yellow thicky oil (300 mg, 44% yield). MS(ES+) C₂₃H₂₉FN₄O₅ requires: 460, found 461 [M+H]⁺; purity: 93% (UV214).

Step 2: Synthesis of tert-butyl4-(5-(2-(4-fluorophenyl)-1,3-dihydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of4-(5-(2-(4-fluorophenyl)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate(700 mg, 1.5 mmol) in 20 mL of THF was cooled to −10° C., followed bythe addition of LiBH₄ (180 mg, 7.5 mmol) slowly. This mixture wasallowed to warm to RT and stirred overnight. The reaction was quenchedby MeOH (3 mL) and then concentrated in vacuo. The residue was purifiedby silica gel column (DCM:MeOH, 10:1) to obtain the desired product (300mg, yield 47%) as a yellow foam. MS (ES+) C₂₂H₂₉FN₄O₄ requires: 432,found 433 [M+H]Y; purity: 67% (UV254).

Step 3: Synthesis of tert-butyl4-(5-(3-(4-fluorophenyl)oxetan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-(2-(4-fluorophenyl)-1,3-dihydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate(650 mg, 1.5 mmol), triphenylphosphine (470 mg, 1.8 mmol), diisopropylazodicarboxylate (360 mg, 1.8 mmol) and ziram (500 mg, 1.8 mmol) in THF(50 mL) was heated at 40° C. overnight under N₂ and concentrated. Theresidue was diluted with EtOAc (40 mL), washed with water (50 mL*2) andbrine, dried over Na₂SO₄ and concentrated. The residue was purified byPrep-HPLC to give the desired product (35 mg, yield 6%) as a whitesolid. MS (ES+) C₂₂H₂₇FN₄O₃ requires: 414, found 359 [M+H−56]⁺; purity:93% (UV214).

Step 4: Synthesis of5-(3-(4-fluorophenyl)oxetan-3-yl)-2-(piperazin-1-yl)pyrimidine

A solution of tert-butyl4-(5-(3-(4-fluorophenyl)oxetan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate(22 mg, 0.05 mmol) in DCM (1 mL) was treated with TFA (0.5 mL) at 60° C.for 3 h and then concentrated under reduced pressure. The residue (30mg, crude, yellow solid, 100% yield) was directly used into the nextstep without further purification. MS (ES+) C₁₇H₁₉FN₄O requires: 314,found 315 [M+H]⁺; purity: 87% (UV254).

Synthesis of(S)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanoland(R)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

Step 1: Synthesis of benzyl4-(5-(1-(5-fluoropyridin-2-yl)-1-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of 2-bromo-5-fluoropyridine (1.3 g, 7.50 mmol) inanhydrous THF (30 mL) was added n-BuLi (2.76 mL, 6.62 mmol) at −78° C.dropwise, and the mixture was stirred at −78° C. for 2 h, followed bythe addition of benzyl4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (1.5 g, 4.41 mmol).The reaction mixture was allowed to warm to RT and stirred overnight.LCMS showed the reaction was completed. The solution was quenched withaqueous NH₄Cl (50 mL) and extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with water (2×50 mL) and brine (50 mL), driedover sodium sulfate, filtered and concentrated. The residue was purifiedby Prep-HPLC to afford the title compound (0.4 g, 20%) as a white solid.MS (ES+) C₂₃H₂₄FN₅O₃ requires: 437, found: 438 [M+H]⁺.

Step 2: Synthesis of(S)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanoland(R)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

A suspension of benzyl4-(5-(1-(5-fluoropyridin-2-yl)-1-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carboxylate(420.0 mg, 0.96 mmol) and Pd/C (200.0 mg) in i-PrOH was exposed to 1 atmH₂ atmosphere (H₂ balloon) and stirred at RT overnight. LCMS showed thereaction was completed. The reaction mixture was filtered through a padof Celite. The filtrate was concentrated and purified by silica gelchromatography (DCM:CH₃OH=10:1) to get the title compound as a whitesolid (153 mg, 53%). MS (ES+) C₁₅H₁₈FN₅O requires: 303, found: 304[M+H]⁺.

The racemate compound (290 mg, 0.96 mmol) was separated by Chiral-HPLCto get(S)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol(peak 1, 80 mg, 28%) and(R)-1-(5-fluoropyridin-2-yl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol(peak 2, 80 mg, 28%).

Synthesis of(S)-tert-butyl4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

2-(1-(4-Fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (138mg, 0.556 mmol), (S)-tert-butyl4-(5-bromopyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (103mg, 0.276 mmol), 2 M sodium carbonate (0.35 mL, 0.700 mmol), andPdCl2(dppf)-DCM adduct (17.3 mg, 0.021 mmol) were taken up in1,4-dioxane (2 mL) in a 2-5 mL microwave vial. The reaction was stirredat 100° C. for 18 hours. Room temperature was attained, the reactionmixture was filtered through a plug of Celite eluting with MeOH, and thefiltrate was concentrated in vacuo while loading onto Celite. Theresidue was purified by MPLC (0-100% EtOAc-hexanes) to give(S)-tert-butyl4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate(107 mg, 0.258 mmol, 94% yield) as an orange gum.

MS (ES+) C₂₂H₂₇FN₄O₃ requires: 414, found: 415 [M+H]⁺.

Synthesis of(S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine

Step 1: Synthesis of(R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide

(R)-2-Methylpropane-2-sulfinamide (0.64 g, 5.28 mmol),2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (0.53 g, 2.76 mmol) andtitanium(IV) isopropoxide (1.5 mL, 5.12 mmol) were stirred in THF (13mL) at 70° C. for 18 hours. Room temperature was attained, saturatedNaCl and EtOAc were added, and the resulting biphasic suspension wasstirred for 5 minutes. The suspension was filtered through Celite toremove the titanium residues, and the organic phase was separated. Theaqueous phase was extracted a second time with EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo while loading onto silica. Purification of theresidue by MPLC (0-20% EtOAc-hexanes) gave(R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide(0.23 g, 0.779 mmol, 28.2% yield) as a yellow oil.

Step 2: Synthesis of tert-butyl4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate

tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.242 g,0.705 mmol) was taken up in THF (3.5 mL) and cooled to −78° C. Asolution of ^(n)BuLi, 2.5 M in hexanes (0.31 mL, 0.775 mmol) was addedat a fast dropwise rate from a syringe. The resulting mixture wasstirred at −78° C. for 15 minutes. A solution of(R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide(0.225 g, 0.762 mmol) in THF (0.5 mL) was added at a fast dropwise ratefrom a syringe. The reaction mixture was stirred at −78° C. for 5minutes before warming to room temperature. After 45 minutes, saturatedNH₄Cl was added and the products extracted into EtOAc (×2). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. Purification of the residue by MPLC (0-80%EtOAc-hexanes) gave tert-butyl4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate(304 mg, 0.543 mmol, 77% yield) as a pale yellow gum. The absolutestereochemistry was assigned randomly.

MS (ES+) C₂₅H₃₃F₄N₅O₃S requires: 559, found: 560 [M+H]⁺.

Step 3: Synthesis of(S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine

tert-Butyl4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate(302 mg, 0.540 mmol) was stirred in 4 M HCl in 1,4-dioxane (3 mL)/MeOH(3 mL) at room temperature for 1 hour. The solvent was removed in vacuoand the residue was partitioned between saturated NaHCO₃ and EtOAc. Theorganic phase was extracted a second time with EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo to give(S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine(190 mg, 0.535 mmol, 99% yield) with ˜88% e.e. Further purification bychiral SFC gave(S)-2,2,2-trifluoro-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine(123.7 mg, 0.348 mmol, 71.2% yield) with ˜99% e.e.

MS (ES+) C₁₆H₁₇F₄N₅ requires: 355, found: 356 [M+H]⁺.

The synthetic protocols that can be used to prepare the compoundsdisclosed herein are indicated below. The NMR and LC MS data obtainedfor compounds disclosed herein are also shown below.

Compound Synthetic LC/MS Number Protocol ¹H NMR (M + 1) 1 1 360 2 1 3863 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 8.15 (d, J = 402 5.2 Hz,1H), 7.34-7.13 (m, 5H), 6.32 (d, J = 5.2 Hz, 1H), 5.95 (s, 1H), 3.93 (s,3H), 3.89 (dd, J = 6.7, 3.6 Hz, 4H), 3.79 (s, 2H), 3.76 (dd, J = 6.4,3.8 Hz, 4H). 4 1 416 5 1 416 6 1 427 7 1 ¹H-NMR (400 MHz, DMSO-d₆ + 1dD₂O) δ ppm 8.33 (s, 452 2H), 7.99 (s, 1H), 7.94 (d, 1H, J = 1.6 Hz),7.86 (s, 1H), 7.81 (s, 1H), 7.30-7.18 (m, 6H), 4.09-4.01 (m, 4H), 3.89-3.83 (m, 4H), 3.84 (s, 3H), 3.80 (s, 2H). 8 1 ¹H-NMR (500 MHz, CDCl₃) δppm 8.24 (s, 2H), 7.91 (s, 466 1H), 7.71, 7.70 (s, s, 2H), 7.58 (s, 1H),7.32-7.29 (m, 2H), 7.247.17 (m, 5H), 6.82 (br. s., 1H), 4.94 (br. s.,1H), 4.61 (br. s., 1H), 4.52-4.49 (m, 2H), 3.96 (s, 3H), 3.87- 3.85(br., 1H), 3.82 (s, 2H), 3.71-3.64 (br, 2H), 1.29 (d, 3H, J = 7.0 Hz). 91 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.35 (s, 2H), 466 8.03 (s, 1H), 7.98(d, 1H, J = 1.2 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.31-7.29 (m, 4H),7.22-7.18 (m, 2H), 4.09-4.06 (m, 5H), 3.96-3.88 (m, 4H), 3.85 (s, 3H),1.58 (d, 3H, J = 7.6 Hz). 10 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.35 (s,2H), 8.03 (s, 466 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H),7.32-7.29 (m, 4H), 7.22-7.17 (m, 2H), 4.09-4.04 (m, 5H), 3.91-3.86 (m,7H), 1.58 (d, 3H, J = 7.2 Hz). 11 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.13 (d,J = 2.3 Hz, 467 1H), 8.02 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.85 (s,1H), 7.80 (d, J = 0.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 7.39-7.25(m, 4H), 7.24-7.15 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 5.79 (d, J = 4.1Hz, 1H), 5.63 (d, J = 4.0 Hz, 1H), 4.13-4.05 (m, 4H), 3.84 (s, 4H),3.71-3.64 (m, 4H). 12 4 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.83 (br. s.,1H), 467 8.40 (s, 2H), 8.10-7.86 (m, 4H), 7.44 (d, 2H, J = 7.6 Hz),7.36-7.15 (m, 4H), 4.10-4.07 (m, 4H), 3.91-3.88 (m, 4H), 1.74 (s, 3H).13 4 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 467 8.01 (s, 1H),7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.43-7.37 (m, 2H), 7.30 (t,2H, J = 8.0 Hz), 7.23-7.16 (m, 2H), 5.01 (s, 1H), 4.11-4.03 (m, 4H),3.92-3.85 (m, 4H), 3.84 (s, 3H), 2.32 (s, 2H). 14 1 1H NMR (300 MHz,DMSO-d6) δ ppm 8.34 (s, 2H), 470 8.03 (d, J = 0.8 Hz, 1H), 7.98 (d, J =1.5 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.34-7.19 (m, 3H),7.19- 7.06 (m, 2H), 4.14-4.05 (m, 4H), 3.90 (dd, J = 6.7, 4.0 Hz, 4H),3.85 (s, 3H), 3.80 (s, 2H). 15 1 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.38(s, 2H), 472 8.04 (s, 1H), 8.00 (d, 1H, J = 1.0 Hz), 7.89 (s, 1H), 7.83(s, 1H), 7.24 (d, 1H, J = 1.0 Hz), 7.21-7.18 (m, 2H), 7.06- 7.03 (m,2H), 4.14-4.12 (m, 4H), 3.94-3.92 (m, 4H), 3.86 (s, 3H). 16 1 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.45 (d, 1H, J = 473 1.6 Hz), 8.34 (s, 2H),8.06 (d, 2H, J = 8.4 Hz), 7.93 (s, 1H), 7.86 (d, 2H, J = 8.4 Hz), 7.62(d, 1H, J = 1.6 Hz), 7.32-7.18 (m, 5H), 4.14 (t, 4H, J = 5.2 Hz), 3.92(t, 4H, J = 5.2 Hz), 3.81 (s, 2H). 17 1 1H NMR (400 MHz, DMSO-d6) δ12.84 (s, 1H), 8.57 (s, 480 2H), 8.10 (s, 1H), 8.02 (d, J = 1.5 Hz, 1H),7.88 (s, 2H), 7.33-7.21 (m, 3H), 7.19-7.12 (m, 1H), 7.05 (td, J = 7.9,1.6 Hz, 1H), 4.24-4.08 (m, 4H), 4.08-3.93 (m, 4H). 18 1 ¹H NMR (400 MHz,DMSO-d₆) δ 8.33 (s, 2H), 8.16 (d, J = 478 1.7 Hz, 1H), 7.88 (s, 1H),7.79-7.70 (m, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.32-7.26 (m, 2H),7.26-7.15 (m, 3H), 7.00-6.92 (m, 2H), 4.11 (dd, J = 6.6, 4.1 Hz, 4H),3.93-3.85 (m, 4H), 3.80 (s, 2H), 3.77 (s, 3H). 19 1 ¹H-NMR (500 MHz,CDCl₃) δ ppm 8.24 (s, 2H), 7.96 (br. 480 s., 1H), 7.70 (s, 1H), 7.60 (s,1H), 7.32-7.17 (m, 5H), 6.84 (br. s., 1H), 4.97 (br. s., 1H), 4.65 (br.s., 1H), 4.54 (br. s., 2H), 3.87 (s, 3H), 3.86-3.82 (m, 5H), 2.41 (s,3H), 1.32 (d, 3H, J = 3.5 Hz). 20 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.28(s, 2H), 8.03 (s, 480 1H), 7.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.82(s, 1H), 7.35-7.25 (m, 4H), 7.24-7.16 (m, 2H), 4.11-4.09 (m, 4H),3.92-3.89 (m, 4H), 3.85 (s, 3H), 1.64 (s, 6H). 21 4 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.39 (s, 2H), 8.01 (s, 481 1H), 7.96 (s, 1H), 7.85 (s,1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.28 (t, 2H, J = 8.0 Hz),7.22-7.15 (m, 2H), 4.11-4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H),2.38 (s, 2H), 1.73 (s, 3H). 22 4 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.40(s, 2H), 8.01 (s, 481 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H),7.44 (s, 1H), 7.42 (s, 1H), 7.28 (t, 2H, J = 8.0 Hz), 7.22-7.15 (m, 2H),4.11-4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H), 2.39 (s, 2H), 1.73(s, 3H). 23 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 2H), 482 8.04 (s,1H), 8.00 (d, 1H, J = 1.6 Hz), 7.89 (s, 1H), 7.83 (s, 1H), 7.42-7.39 (m,2H), 7.25-7.20 (m, 3H), 5.50 (s, 1H), 5.41 (s, 1H), 4.15-4.12 (m, 4H),4.00-3.97 (m, 4H), 3.86 (s, 3H). 24 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.40 (s, 2H), 8.03 (s, 482 1H), 7.97 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H),7.81 (s, 1H), 7.46-7.44 (m, 2H), 7.33-7.29 (m, 2H), 7.22-7.19 (m, 2H),5.81 (s, 1H), 4.10-4.07 (m, 4H), 3.92-3.87 (m, 4H), 3.85 (s, 3H), 1.83(s, 3H). 25 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.40 (s, 2H), 8.03 (s, 4821H), 7.97 (d, 1H, J = 2.0 Hz), 7.87 (s, 1H), 7.81 (s, 1H), 7.46-7.43 (m,2H), 7.33-7.29 (m, 2H), 7.22-7.21 (m, 2H), 5.81 (s, 1H), 4.10-4.07 (m,4H), 3.92-3.89 (m, 4H), 3.85 (s, 3H), 1.82 (s, 3H). 26 3 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 12.85 (s, 1H), 485 8.41 (s, 2H), 8.11 (s, 1H), 8.01(d, 1H, J = 1.6 Hz), 7.89- 7.87 (m, 2H), 7.48-7.45 (m, 2H), 7.25 (d, 1H,J = 1.6 Hz), 7.13-7.09 (m, 2H), 4.11-4.08 (m, 4H), 3.92-3.89 (m, 4H),2.45 (br. s., 2H), 1.73 (s, 3H). 27 4 1H-NMR (400 MHz, CDCl3) δ ppm 8.35(s, 2H), 7.90 (s, 485 1H), 7.70-7.69 (m, 2H), 7.56 (s, 1H), 7.38-7.35(m, 2H), 7.05-7.00 (m, 2H), 6.77 (d, 1H, J = 2.0 Hz), 5.13 (s, 1H),4.15-4.12 (m, 4H), 4.02-3.99 (m, 4H), 3.99 (s, 3H). 28 4 1H-NMR (400MHz, CDCl3) δ ppm 8.35 (s, 2H), 7.90 (s, 485 1H), 7.70-7.69 (m, 2H),7.57 (s, 1H), 7.38-7.35 (m, 2H), 7.05-7.00 (m, 2H), 6.77 (d, 1H, J = 2.0Hz), 5.13 (s, 1H), 4.15-4.12 (m, 4H), 4.02-3.99 (m, 4H), 3.95 (s, 3H).29 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s., 486 1H), 8.39 (s,2H), 8.10-8.00 (br, 1H), 8.00 (d, 1H, J = 1.2 Hz), 7.95-7.85 (br, 1H),7.86 (s, 1H), 7.47-7.44 (dd, 2H, J = 8.8, 5.6 Hz), 7.24 (d, 1H, J = 1.2Hz), 7.12 (t, 2H, J = 8.8 Hz), 5.90 (s, 1H), 4.09-4.07 (m, 4H),3.91-3.88 (m, 4H), 1.81 (s, 3H). 30 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm12.81 (br. s., 1H), 486 8.39 (s, 2H), 8.09 (br. s., 1H), 8.00 (d, 1H, J= 1.2 Hz), 7.87-7.86 (m, 2H), 7.47-7.44 (m, 2H), 7.24 (d, 1H, J = 1.2Hz), 7.12 (t, 2H, J = 8.8 Hz), 5.90 (s, 1H), 4.09-4.07 (m, 4H),3.91-3.88 (m, 4H), 1.81 (s, 3H). 31 3 1H-NMR (500 MHz, DMSO-d6) δ ppm8.34 (s, 2H), 486 8.03 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s,1H), 7.44-7.41 (m, 2H), 7.22 (s, 1H), 7.18-7.14 (m, 2H), 6.01 (d, 1H, J= 3.5 Hz), 5.68 (d, 1H, J = 3.0 Hz), 4.09 (br. s., 4H), 3.91 (br. s.,4H), 3.85 (s, 3H). 32 3 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.34 (s, 2H),486 8.03 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.44- 7.41(m, 2H), 7.22 (s, 1H), 7.18-7.14 (m, 2H), 6.01 (s, 1H), 5.68 (s, 1H),4.09 (br. s., 4H), 3.91 (br. s., 4H), 3.85 (s, 3H). 33 1 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.37 (d, 1H, J = 491 1.2 Hz), 8.34 (s, 2H), 7.98 (s,1H), 7.96-7.89 (m, 5H), 7.56 (s, 1H), 7.30-7.20 (m, 6H), 4.14 (t, 4H, J= 6.0 Hz), 3.87 (t, 4H, J = 5.2 Hz), 3.81 (s, 2H). 34 4 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.40 (s, 2H), 495 8.26 (d, 1H, J = 2.0 Hz), 7.90-7.86 (m,3H), 7.46-7.41 (m, 3H), 7.31-7.18 (m, 5H), 4.13-4.10 (m, 4H), 3.91- 3.89(m, 4H), 3.31-3.29 (br, 2H), 1.73 (s, 3H). 35 4 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.40 (s, 2H), 495 8.08 (s, 1H), 7.97 (s, 1H), 7.86 (s,1H), 7.81 (s, 1H), 7.42 (d, 2H, J = 8.0 Hz), 7.31-7.27 (m, 2H),7.22-7.18 (m, 2H), 4.12 (q, 2H, J = 7.2 Hz), 4.09-4.07 (m, 4H), 3.92-3.88 (m, 4H), 2.70-2.60 (m, 2H), 1.74 (s, 3H), 1.39 (t, 3H, J = 7.6 Hz).36 4 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 2H), 495 8.01 (s, 1H),7.96 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.45-7.39 (m, 2H), 7.31 (t,2H, J = 8.0 Hz), 7.23-7.17 (m, 2H), 4.11 (s, 1H), 4.10-4.04 (m, 4H),3.92-3.86 (m, 4H), 3.84 (s, 3H), 2.11 (s, 6H). 37 4 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.41 (s, 2H), 495 8.02 (s, 1H), 7.97-7.96 (m, 1H), 7.85(s, 1H), 7.80 (s, 1H), 7.45-7.39 (m, 2H), 7.31 (t, 2H, J = 8.0 Hz),7.23- 7.17 (m, 2H), 4.11 (s, 1H), 4.10-4.04 (m, 4H), 3.92-3.86 (m, 4H),3.84 (s, 3H), 2.12 (s, 6H). 38 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.40(s, 2H), 496 8.27 (d, 1H, J = 1.6 Hz), 7.90 (s, 1H), 7.84-7.82 (m, 2H),7.48-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.27-7.23 (m, 1H), 7.14-7.10 (m,2H), 5.89 (s, 1H), 4.14-4.11 (m, 4H), 3.92- 3.90 (m, 4H), 1.81 (s, 3H).39 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 2H), 7.90 (s, 498 1H), 7.70(s, 2H), 7.57 (s, 1H), 7.21 (dd, 2H, J = 8.0, 4.0 Hz), 7.01-6.96 (m,2H), 6.78 (s, 1H), 4.17-4.14 (m, 4H), 4.02-3.99 (m, 4H), 3.95 (s, 3H),1.67 (s, 6H). 40 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.22 (s, 2H), 7.89 (s,498 1H), 7.69, 7.68 (s, s, 2H), 7.56 (s, 1H), 7.18-7.15 (m, 2H),7.01-6.97 (m, 2H), 6.77 (d, 1H, J = 1.6 Hz), 4.15- 4.13 (m, 4H),4.01-3.98 (m, 4H), 3.95 (s, 3H), 3.64 (t, 1H, J = 8.0 Hz), 2.05-1.98 (m,2H), 0.92 (t, 3H, J = 8.0 Hz). 41 3 ¹H-NMR (400 MHz, CDCl₃-d₆) δ ppm8.22 (s, 2H), 7.89 (s, 498 1H), 7.69, 7.68 (s, s, 2H), 7.56 (s, 1H),7.18-7.15 (m, 2H), 7.01-6.97 (m, 2H), 6.77 (d, 1H, J = 1.6 Hz), 4.15-4.13 (m, 4H), 4.01-3.98 (m, 4H), 3.95 (s, 3H), 3.64 (t, 1H, J = 7.6 Hz),2.04-1.99 (m, 2H), 0.92 (t, 3H, J = 7.6 Hz). 43 4 ¹H-NMR (400 MHz,DMSO-d6) δ ppm 8.39 (s, 2H), 8.02 (s, 499 1H), 7.96 (s, 1H), 7.86 (s,1H), 7.80 (s, 1H), 7.47-7.43 (m, 2H), 7.21 (s, 1H), 7.12-7.07 (m, 2H),4.11-4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H), 1.72 (s, 3H). 44 4¹H-NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 2H), 8.02 (s, 1H), 499 7.96 (s,1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.47-7.43 (m, 2H), 7.21 (s, 1H),7.12-7.07 (m, 2H), 4.11-4.05 (m, 4H), 3.92-3.86 (m, 4H), 3.84 (s, 3H),1.72 (s, 3H). 42 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 2H), 8.12 (s,499 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.24-7.20 (m, 2H), 7.01- 7.96 (m,2H), 6.48 (s, 1H), 4.50 (br. s., 4H), 4.02-4.00 (m, 4H), 3.99 (s, 3H),1.67 (s, 6H). 45 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.38 (s, 2H), 7.91 (s,500 1H), 7.70 (s, 2H), 7.57 (s, 1H), 7.41 (dd, 2H, J = 8.0, 4.0 Hz),7.05-7.01 (m, 2H), 6.79 (s, 1H), 4.17-4.15 (m, 4H), 4.05-4.02 (m, 4H),3.95 (s, 3H), 1.94 (s, 3H). 46 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.38 (s,2H), 7.89 (s, 500 1H), 7.69 (s, 2H), 7.57 (s, 1H), 7.41 (dd, 2H, J =8.0, 4.0 Hz), 7.05-7.01 (m, 2H), 6.77 (d, 1H, J = 1.2 Hz), 4.17- 4.15(m, 4H), 4.05-4.02 (m, 4H), 3.95 (s, 3H), 1.94 (s, 3H). 47 3 1H-NMR (400MHz, CDCl3) δ ppm 8.37 (s, 2H), 7.88 (s, 500 1H), 7.67 (s, 2H),7.65-7.63 (m, 1H), 7.55 (s, 1H), 7.32-7.29 (m, 1H), 7.21-7.17 (m, 1H),7.03-6.98 (m, 1H), 6.76 (s, 1H), 4.14-4.11 (m, 4H), 4.01-3.99 (m, 4H),3.93 (s, 3H), 2.90 (d, 1H, J = 4.0 Hz), 1.96 (s, 3H). 48 3 1H-NMR (400MHz, CDCl3) δ ppm 8.37 (s, 2H), 7.88 (s, 500 1H), 7.69 (s, 2H), 7.64 (t,1H, J = 7.2 Hz), 7.56 (s, 1H), 7.31-7.28 (m, 1H), 7.19 (d, 1H, J = 7.6Hz), 7.01 (dd, 1H, J = 11.6, 8.4 Hz), 6.77 (s, 1H), 4.15-4.13 (m, 4H),4.03-4.00 (m, 4H), 3.94 (s, 3H), 2.74 (d, 1H, J = 4.4 Hz), 1.97 (s, 3H).49 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.34 (s, 2H), 500 8.03 (s, 1H),7.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.35-7.32 (m, 2H),7.23 (d, 1H, J = 1.6 Hz), 7.15- 7.10 (m, 2H), 4.93 (t, 1H, J = 4.8 Hz),4.12-4.06 (m, 4H), 4.02-3.97 (m, 1H), 3.94-3.86 (m, 6H), 3.85 (s, 3H).50 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.34 (s, 2H), 8.03 (s, 1H), 5007.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.35-7.32 (m, 2H),7.23 (d, 1H, J = 1.6 Hz), 7.15- 7.10 (m, 2H), 4.93 (t, 1H, J = 4.8 Hz),4.12-4.06 (m, 4H), 4.02-3.97 (m, 1H), 3.94-3.86 (m, 6H), 3.85 (s, 3H).51 3 1H-NMR (400 MHz, CDCl3) δ ppm 8.37 (br. s., 2H), 7.90 (br. s., 5012H), 7.39 (br. s., 2H), 7.03 (br. s., 3H), 6.23 (s, 1H), 4.18-4.14 (m,4H), 4.04-4.01 (m, 4H), 2.49 (s, 1H), 2.33 (s, 3H), 1.92 (s, 3H). 52 31H-NMR (400 MHz, CDCl3) δ ppm 8.37 (s, 2H), 7.92, 501 7.91 (s, s, 2H),8.42-7.38 (m, 2H), 7.05-7.00 (m, 3H), 6.23 (s, 1H), 4.18-4.14 (m, 4H),4.04-4.01 (m, 4H), 2.36 (s, 1H), 2.34 (s, 3H), 1.93 (s, 3H). 53 3 1H-NMR(400 MHz, DMSO-d6) δ ppm 8.48 (d, 1H, J = 501 4.8 Hz), 8.41 (d, 1H, J =3.2 Hz), 8.38 (s, 2H), 8.03 (s, 1H), 7.99 (d, 1H, J = 1.6 Hz), 7.87 (s,1H), 7.82 (s, 1H), 7.79- 7.76 (m, 1H), 7.23 (d, 1H, J = 1.6 Hz), 6.25(s, 1H), 4.11- 4.08 (m, 4H), 3.94-3.91 (m, 4H), 3.85 (s, 3H), 1.88 (s,3H). 54 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, 1H, J = 501 4.8 Hz),8.41 (d, 1H, J = 3.2 Hz), 8.38 (s, 2H), 8.03 (s, 1H), 7.99 (d, 1H, J =1.6 Hz), 7.87 (s, 1H), 7.82 (d, 1H, J = 0.8 Hz), 7.79-7.76 (m, 1H), 7.23(d, 1H, J = 2.0 Hz), 6.25 (s, 1H), 4.11-4.08 (m, 4H), 3.93-3.91 (m, 4H),3.85 (s, 3H), 1.87 (s, 3H). 55 1 ¹H-NMR (500 MHz, CDCl₃) δ ppm 8.47 (s,2H), 7.92 (s, 502 1H), 7.72, 7.70 (s, s, 2H), 7.57 (s, 1H), 7.20-7.17(m, 1H), 7.11-7.02 (m, 3H), 6.83 (br. s., 1H), 4.97-4.95 (m, 1H),4.62-4.47 (m, 3H), 3.97-3.95 (m, 4H), 3.76-3.72 (m, 2H), 1.33 (d, 3H, J= 6.5 Hz). 56 1 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 8.03 (s, 5031H), 7.98 (d, J = 1.5 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 0.8 Hz, 1H),7.22 (d, J = 1.7 Hz, 1H), 7.20-7.10 (m, 4H), 4.15-4.04 (m, 4H),3.98-3.88 (m, 4H), 3.86 (s, 3H). 57 3 1H-NMR (400 MHz, DMSO-d6) δ ppm12.84 (s, 1H), 504 8.38 (s, 2H), 8.05-8.01 (m, 3H), 7.88 (s, 1H),7.83-7.77 (m, 1H), 7.26 (s, 1H), 7.14-7.09 (m, 2H), 6.05 (s, 1H),4.12-4.09 (m, 4H), 3.93-3.91 (m, 4H), 1.84 (s, 3H). 58 3 1H-NMR (400MHz, DMSO-d6) δ ppm 12.80 (br s, 1H), 504 8.34 (s, 2H), 8.02 (s, 1H),8.02 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.83-7.77 (m, 1H), 7.26 (d,1H, J = 1.2 Hz), 7.14- 7.08 (m, 2H), 6.05 (br s, 1H), 4.12-4.09 (m, 4H),3.94- 3.91 (m, 4H), 1.84 (s, 3H). 59 3 1H-NMR (400 MHz, DMSO-d6) δ ppm8.39 (s, 2H), 510 8.21 (s, 1H), 7.88 (s, 1H), 7.71 (d, 2H, J = 7.6 Hz),7.47- 7.42 (m, 3H), 7.19 (d, 2H, J = 7.6 Hz), 7.13-7.09 (m, 2H), 5.89(br. s., 1H), 4.11 (br. s., 4H), 3.90 (s, 4H), 2.30 (s, 3H), 1.81 (s,3H). 60 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.94 (d, 1H, J = 511 2.4 Hz),8.41 (s, 2H), 8.34 (d, 1H, J = 1.6 Hz), 8.12-8.10 (m, 1H), 7.91 (s, 1H),7.54 (d, 1H, J = 1.2 Hz),7.48-7.45 (m, 2H), 7.30-7.27 (m, 1H), 7.15-7.11(m, 2H), 5.90 (s, 1H), 4.13-4.11 (m, 4H), 3.93-3.90 (m, 4H), 2.47 (s,3H), 1.82 (s, 3H). 61 1 1H-NMR (400 MHz, CDCl3) δ ppm 8.26 (s, 2H), 7.90(s, 512 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.18-7.05 (m, 4H), 6.77 (d, 1H,J = 1.6 Hz), 5.25 (d, 2H, J = 6.0 Hz), 5.10 (d, 2H, J = 6.0 Hz),4.17-4.14 (m, 4H), 4.05-4.01 (m, 4H), 3.95 (s, 3H). 62 4 1H-NMR (400MHz, DMSO-d6) δ ppm 8.40 (s, 2H), 513 8.26 (s, 1H), 7.90-7.86 (m, 3H),7.47-7.44 (m, 3H), 7.26- 7.21 (m, 2H), 7.12-7.08 (m, 2H), 4.13-4.09 (m,4H), 3.92-3.89 (m, 4H), 2.56-2.54 (br, 2H), 1.72 (s, 3H). 63 4 1H-NMR(400 MHz, DMSO-d6) δ ppm 8.40 (s, 2H), 513 8.08 (s, 1H), 7.97 (s, 1H),7.86 (s, 1H), 7.82 (s, 1H), 7.45 (dd, 2H, J = 6.0, 8.8 Hz), 7.22 (s,1H), 7.12-7.08 (m, 2H), 4.12 (q, 2H, J = 7.2 Hz), 4.10-4.07 (m, 4H),3.91-3.88 (m, 4H), 2.54-2.50 (br, 2H), 1.72 (s, 3H), 1.40 (t, 3H, J =7.2 Hz). 64 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.38 (s, 2H), 7.92 (s, 5141H), 7.83 (d, 1H, J = 1.6 Hz), 7.59-7.55 (m, 2H), 7.43- 7.39 (m, 2H),7.13-7.09 (m, 2H), 7.05-7.01 (m, 2H), 6.91 (d, 1H, J = 1.6 Hz),4.18-4.16 (m, 4H), 4.04-4.02 (m, 4H), 2.21 (s, 1H), 1.94 (s, 3H). 65 3¹H-NMR (400 MHz, CDCl₃-d₆) δ ppm 8.38 (s, 2H), 7.92 (s, 514 1H), 7.83(d, 1H, J = 1.6 Hz), 7.59-7.55 (m, 2H), 7.43-7.39 (m, 2H), 7.13-7.09 (m,2H), 7.05-7.01 (m, 2H), 6.91 (d, 1H, J = 1.6 Hz), 4.18-4.16 (m, 4H),4.04-4.02 (m, 4H), 2.21 (s, 1H), 1.94 (s, 3H). 66 3 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.41 (s, 2H), 514 8.35 (d, 1H, J = 1.6 Hz), 7.92 (s, 1H),7.76-7.69 (m, 2H), 7.54 (d, 1H, J = 1.2 Hz), 7.49-7.42 (m, 3H),7.15-7.06 (m, 3H), 5.89 (s, 1H), 4.14 (t, 4H, J = 6.0 Hz), 3.92 (t, 4H,J = 5 .2 Hz), 1.82 (s, 3H). 67 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.29 (s,2H), 7.90 (s, 514 1H), 7.69 (d, 2H, J = 1.6 Hz), 7.56 (s, 1H), 7.35-7.31(m, 2H), 7.04-6.99 (m, 2H), 6.77 (d, 1H, J = 1.6 Hz), 4.16- 4.14 (m,4H), 4.03-4.01 (m, 4H), 3.95 (s, 3H), 3.16 (s, 3H), 1.82 (s, 3H). 68 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.31 (s, 2H), 8.03 (s, 514 1H), 7.97 (d,1H, J = 1.6 Hz), 7.87 (s, 1H), 7.81 (s, 1H), 7.41-7.38 (m, 2H), 7.22 (d,1H, J = 1.6 Hz), 7.18- 7.13 (m, 2H), 4.11-4.09 (m, 4H), 3.94-3.91 (m,4H), 3.85 (s, 3H), 3.09 (s, 3H), 1.81 (s, 3H). 69 3 ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.36 (s, 2H), 7.89 (s, 514 1H), 7.69 (s, 2H), 7.56 (s, 1H),7.40-7.37 (m, 2H), 7.05- 6.99 (m, 2H), 6.77 (d, 1H, J = 1.2 Hz),4.16-4.13 (m, 4H), 4.03-4.00 (m, 4H), 3.95 (s, 3H), 2.26 (q, 2H, J = 8.0Hz), 2.07 (br. s., 1H), 0.91 (t, 3H, J = 8.0 Hz). 70 3 ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.36 (s, s, 2H), 7.89 (s, 514 1H), 7.69 (s, 2H), 7.56 (s,1H), 7.40-7.37 (m, 2H), 7.05-7.00 (m, 2H), 6.77 (d, 1H, J = 1.6 Hz),4.16-4.13 (m, 4H), 4.03-4.00 (m, 4H), 3.95 (s, 3H), 2.26 (q, 2H, J = 8.0Hz), 2.07 (br. s., 1H), 0.91 (t, 3H, J = 8.0 Hz). 71 3 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.40 (s, 2H), 514 7.94 (s, 1H), 7.89 (s, 1H), 7.84 (d,1H, J = 1.2 Hz), 7.46 (dd, 2H, J = 5.6, 8.8 Hz), 7.15-7.09 (m, 2H),5.93-5.87 (br, 1H), 4.11-4.08 (m, 4H), 3.92-3.89 (m, 4H), 3.78 (s, 3H),2.32 (s, 3H), 1.82 (s, 3H). 72 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.40(s, 2H), 514 7.94 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H, J = 1.6 Hz), 7.48-7.45 (m, 2H), 7.15-7.09 (m, 3H), 5.89 (s, 1H), 4.11-4.08 (m, 4H),3.92-3.89 (m, 4H), 3.78 (s, 3H), 2.32 (s, 3H), 1.82 (s, 3H). 73 1 1H-NMR(400 MHz, DMSO-d6) δ ppm 8.32 (s, 2H), 514 8.00 (s, 1H), 7.95 (s, 1H),7.85 (s, 1H), 7.77 (s, 1H), 7.35-7.29 (m, 2H), 7.20 (s, 1H), 7.11 (t,2H, J = 8.0 Hz), 4.92 (t, 1H, J = 4.0 Hz), 4.69-4.56 (m, 2H), 4.39-4.26(m, 2H), 4.07 (q, 1H, J = 8.0 Hz), 3.84 (s, 3H), 3.83-3.78 (m, 1H),3.76-3.58 (m, 2H), 3.55-3.40 (m, 2H), 1.55 (d, 3H, J = 8.0 Hz). 74 11H-NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 2H), 514 8.00 (s, 1H),7.96-7.95 (m, 1H), 7.85 (s, 1H), 7.78-7.77 (m, 1H), 7.34-7.29 (m, 2H),7.21-7.20 (m, 1H), 7.14-7.08 (m, 2H), 4.92 (t, 1H, J = 4.0 Hz),4.67-4.55 (m, 2H), 4.38- 4.26 (m, 2H), 4.07 (q, 1H, J = 8.0 Hz), 3.84(s, 3H), 3.83-3.78 (m, 1H), 3.77-3.58 (m, 2H), 3.55-3.42 (m, 2H), 1.55(d, 3H, J = 8.0 Hz). 75 3 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 2H),514 8.09 (s, 1H), 7.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.82 (s, 1H),7.48-7.45 (m, 2H), 7.23 (d, 1H, J = 2.0 Hz), 7.15- 7.12 (m, 2H), 5.89(s, 1 H), 4.15-4.08 (m, 6H), 3.92 (t, 4H, J = 6.4 Hz), 1.82 (s, 3H),1.42 (t, 3H, J = 7.2 Hz). 76 1 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s,2H), 514 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.85 (s, 1H), 7.81 (s, 1H),7.49-7.44 (m, 2H), 7.22-7.19 (m, 1H), 7.15-7.09 (m, 2H), 5.85 (s, 1H),4.85-4.77 (m, 1H), 4.64-4.56 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.37 (m,1H), 3.85 (s, 3H), 3.78- 3.71 (m, 1H), 3.64-3.49 (m, 2H), 1.81 (s, 3H),1.15 (d, 3H, J = 8.0 Hz). 77 1 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s,2H), 514 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.85 (s, 1H), 7.81 (s, 1H),7.49-7.44 (m, 2H), 7.22-7.19 (m, 1H), 7.15-7.09 (m, 2H), 5.85 (s, 1H),4.85-4.77 (m, 1H), 4.64-4.56 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.37 (m,1H), 3.85 (s, 3H), 3.78- 3.71 (m, 1H), 3.64-3.49 (m, 2H), 1.81 (s, 3H),1.15 (d, 3H, J = 8.0 Hz). 78 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s,2H), 8.04 (s, 514 1H), 7.98 (d, 1H, J = 1.2 Hz), 7.87 (s, 1H), 7.82 (s,1H), 7.30-7.23 (m, 3H), 7.11-7.09 (m, 2H), 5.08-5.05 (m, 1H), 4.11-4.08(m, 4H), 3.92-3.87 (m, 4H), 3.85 (s, 3H), 3.78-3.74 (m, 2H), 1.58 (s,3H). 79 3 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 2H), 514 8.04 (s,1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.30-7.23 (m, 3H),7.13-7.09 (m, 2H), 5.08-5.05 (br. s., 1H), 4.10 (br. s., 4H), 3.90 (br.s., 4H), 3.85 (s, 3H), 3.78-3.74 (m, 2H), 1.58 (s, 3H). 80 3 1H-NMR (400MHz, DMSO-d6) δ ppm 8.22 (s, 2H), 514 8.04 (s, 1H), 7.99 (d, 1H, J = 1.2Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.65 (dd, 1H, J = 8.4, 6.0 Hz), 7.23(d, 1H, J = 1.2 Hz), 7.03 (td, 1H, J = 8.4, 2.8 Hz), 6.96 (dd, 1H, J =10.0, 2.8 Hz), 5.81 (s, 1H), 4.11-4.08 (m, 4H), 3.92-3.89 (m, 4H), 3.85(s, 3H), 2.07 (s, 3H), 1.81 (s, 3H). 81 3 1H-NMR (400 MHz, DMSO-d6) δppm 8.40 (s, 2H), 516 8.01 (s, 1H), 7.90 (s, 1H), 7.52-7.40 (m, 2H),7.23-7.19 (m, 2H), 7.15-7.10 (m, 2H), 6.78 (s, 1H), 5.89 (s, 1H), 4.10(br. s., 4H), 3.91 (br. s., 4H), 2.45 (s, 3H), 1.82 (s, 3H). 82 3 1H-NMR(400 MHz, DMSO-d6) δ ppm 8.40 (s, 2H), 516 8.02 (s, 1H, J = 1.6 Hz),7.90 (s, 1H), 7.49-7.45 (m, 2H), 7.23-7.19 (m, 2H), 7.15-7.10 (m, 2H),6.80-6.76 (m, 1H), 5.89 (s, 1H), 4.11-4.05 (m, 4H), 3.95-3.86 (m, 4H),2.45 (s, 3H), 1.82 (s, 3H). 83 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.41(s, 2H), 516 8.03 (s, 1H), 7.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.82(s, 1H), 7.46 (d, 1H, J = 8.8 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.22 (d,1H, J = 1.6 Hz), 5.93 (s, 1H), 4.10-4.08 (m, 4H), 3.92-3.90 (m, 4H),3.85 (s, 3H), 1.82 (s, 3H). 84 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.41(s, 2H), 516 8.03 (s, 1H), 7.98 (d, 1H, J = 1.2 Hz), 7.87 (s, 1H), 7.82(s, 1H), 7.46 (d, 1H, J = 8.8 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.22 (d,1H, J = 1.6 Hz), 5.93 (s, 1H), 4.10-4.08 (m, 4H), 3.92-3.90 (m, 4H),3.85 (s, 3H), 1.82 (s, 3H). 85 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.32(s, 2H), 8.04 (s, 517 1H), 7.99 (d, 1H, J = 1.2 Hz), 7.87 (s, 1H),7.82-7.77 (m, 2H), 7.23 (d, 1H, J = 1.2 Hz), 7.14-7.08 (m, 2H), 4.10-4.07 (m, 4H), 3.92-3.88 (m, 4H), 3.85 (s, 3H), 1.73 (s, 3H). 86 3 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.32 (s, 2H), 8.04 (s, 517 1H), 7.99 (s, 1H),7.87 (s, 1H), 7.82-7.77 (m, 2H), 7.23 (s, 1H), 7.14-7.08 (m, 2H),4.10-4.07 (m, 4H), 3.92- 3.88 (m, 4H), 3.85 (s, 3H), 1.73 (s, 3H). 87 31H-NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 2H), 517 8.10 (d, 1H, J = 1.2Hz), 7.96 (s, 1H), 7.91 (s, 1H), 7.47- 7.44 (m, 2H), 7.29 (d, 1H, J =1.2 Hz), 7.12 (t, 2H, J = 8.8 Hz), 5.89 (s, 1H), 4.10-4.08 (m, 4H),3.91-3.89 (m, 4H), 2.65 (s, 3H), 1.81 (s, 3H). 88 3 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.38 (s, 1H), 517 8.37 (s, 1H), 8.10 (d, 1H, J = 1.2 Hz),7.96 (d, 1H, J = 1.6 Hz), 7.91 (d, 1H, J = 2.0 Hz), 7.46-7.43 (m, 2H),7.28 (s, 1H), 7.12 (t, 2H, J = 8.8 Hz), 5.92 (br. s., 1H), 4.09 (br. s.,4H), 3.89 (br. s., 4H), 2.65 (s, 3H), 1.80 (s, 3H). 89 3 1H-NMR (400MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 518 8.39 (s, 2H), 8.07 (s, 1H), 7.98(s, 1H), 7.48-7.44 (m, 2H), 7.15-7.10 (m, 2H), 7.00 (s, 1H), 5.90 (s,1H), 3.91 (s, 3H), 3.87 (s, 8H), 1.82 (s, 3H). 90 3 1H-NMR (400 MHz,DMSO-d6) δ ppm 8.40 (s, 1H), 518 8.39 (s, 2H), 8.07 (s, 1H), 7.98 (s,1H), 7.48-7.45 (m, 2H), 7.15-7.10 (m, 2H), 7.00 (s, 1H), 5.90 (s, 1H),3.91 (s, 3H), 3.87 (s, 8H), 1.82 (s, 3H). 91 3 1H-NMR (400 MHz, DMSO-d6)δ ppm 8.37 (s, 2H), 518 8.04 (s, 1H), 7.99 (d, 1H, J = 1.6 Hz), 7.87 (s,1H), 7.82 (d, 1H, J = 1.2 Hz), 7.41-7.33 (m, 1H), 7.23 (d, 1H, J = 1.6Hz), 7.05-6.98 (m, 2H), 6.10 (s, 1H), 4.12-4.09 (m, 4H), 3.93-3.91 (m,4H), 3.85 (s, 3H), 1.90 (s, 3H). 92 3 1H-NMR (400 MHz, DMSO-d6) δ ppm8.37 (s, 2H), 8.04 (s, 518 1H), 7.99 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H),7.82 (s, 1H), 7.41-7.34 (m, 1H), 7.23 (d, 1H, J = 1.6 Hz), 7.05- 6.98(m, 2H), 6.10 (s, 1H), 4.12-4.09 (m, 4H), 3.93-3.90 (m, 4H), 3.85 (s,3H), 1.90 (s, 3H). 93 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (s, 2H),8.03 (s, 518 1H), 7.98 (d, 1H, J = 1.6 Hz), 7.87 (s, 1H), 7.83-7.77 (m,2H), 7.23 (d, 1H, J = 1.2 Hz), 7.14-7.08 (m, 2H), 6.04 (s, 1H),4.11-4.08 (m, 4H), 3.93-3.90 (m, 4H), 3.85 (s, 3H), 1.84 (s, 3H). 95 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.37 (s, 2H), 8.02 (s, 518 1H), 7.97 (s,1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.47 (dd, 2H, J = 8.4, 5.6 Hz),7.22-7.16 (m, 3H), 6.40 (s, 1H), 4.86 (td, 2H, J = 45.2, 10.0 Hz), 4.09(br. s., 4H), 3.92 (br. s., 4H), 3.84 (s, 3H). 96 3 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.38 (s, 2H), 8.02 (s, 518 1H), 7.97 (s, 1H), 7.86 (s,1H), 7.81 (s, 1H), 7.48 (br. s., 2H), 7.22-7.16 (m, 3H), 6.39 (s, 1H),4.86 (td, 2H, J = 45.6, 10.0 Hz), 4.09 (br. s., 4H), 3.92 (br. s., 4H),3.84 (s, 3H). 97 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 2H), 8.02 (s,518 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.88 (s, 1H), 7.79 (d, J = 0.8 Hz,1H), 7.33-7.20 (m, 3H), 7.20-7.11 (m, 1H), 7.10-7.01 (m, 1H), 5.02 (t, J= 5.2 Hz, 1H), 4.67 (d, J = 11.0 Hz, 2H), 4.40 (d, J = 10.2 Hz, 2H),3.95 - 3.71 (m, 6H), 3.65-3.48 (m, 3H). 94 4 ¹H-NMR (400 MHz, DMSO-d₆) δppm δ 8.34 (s, 2H), 518 8.03 (s, 1H), 7.98 (d, 1H, J = 1.2 Hz), 7.87 (s,1H), 7.83- 7.77 (m, 2H), 7.23 (d, 1H, J = 1.2 Hz), 7.14-7.09 (m, 2H),6.04 (s, 1H), 4.11-4.08 (m, 4H), 3.93-3.90 (m, 4H), 3.85 (s, 3H), 1.84(s, 3H). 98 1 519 103 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.39 (s, 2H), 7.90(s, 526 1H), 7.70 (s, 2H), 7.56 (s, 1H), 7.46-7.43 (m, 2H), 7.05- 7.00(m, 2H), 6.78 (d, 1H, J = 1.2 Hz), 4.17-4.14 (m, 4H), 4.05-4.02 (m, 4H),3.95 (s, 3H), 1.93 (br. s., 1H), 0.66-0.62 (m, 2H), 0.49-0.45 (m, 2H).104 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.39 (s, 2H), 7.91 (s, 526 1H), 7.70(s, 2H), 7.57 (s, 1H), 7.46-7.43 (m, 2H), 7.05- 7.01 (m, 2H), 6.79 (s,1H), 4.18-4.15 (m, 4H), 4.05-4.02 (m, 4H), 3.95 (s, 3H), 1.90 (br. s.,1H), 0.67-0.63 (m, 2H), 0.48-0.44 (m, 2H). 105 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.56 (s, 2H), 8.04 (s, 532 1H), 8.00 (s, 1H), 7.87 (s,1H), 7.83 (s, 1H), 7.27-7.24 (m, 3H), 7.17-7.14 (m, 1H), 7.06-7.02 (m,1H), 4.97 (d, 1H, J = 4.4 Hz), 4.15-4.13 (m, 4H), 4.00 (br. s., 7H),1.05 (d, 3H, J = 5.6 Hz). 111 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.40 (s,2H), 8.02 (s, 535 1H), 7.97 (d, 1H, J = 1.6 Hz), 7.86 (s, 1H), 7.81 (s,1H), 7.54-7.50 (m, 2H), 7.22-7.17 (m, 3H), 6.75 (t, 1H, J = 55.2 Hz),4.10-4.05 (m, 4H), 3.93-3.90 (m, 4H), 3.84 (s, 3H), 2.70 (s, 2H). 112 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.39 (s, 2H), 8.02 (s, 535 1H), 7.99 (d,1H, J = 1.2 Hz), 7.86 (s, 1H), 7.81 (s, 1H), 7.52 (dd, 2H, J = 5.6, 8.8Hz), 7.22-7.17 (m, 3H), 6.74 (t, 1H, J = 55.2 Hz), 4.10-4.07 (m, 4H),3.90-3.90 (m, 4H), 3.84 (s, 3H), 2.69 (s, 2H). 117 3 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.35 (s, 2H), 8.02 (s, 536 1H), 7.97 (d, 1H, J = 1.6 Hz),7.86 (s, 1H), 7.81 (s, 1H), 7.50 (dd, 2H, J = 5.2, 8.8 Hz), 7.25-7.20(m, 3H), 6.78 (s, 1H), 6.70 (t, 1H, J = 54.4 Hz), 4.10-4.08 (m, 4H),3.94-3.93 (m, 4H), 3.84 (s, 3H). 118 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.35 (s, 2H), 8.02 (s, 536 1H), 7.99 (d, 1H, J = 1.2 Hz), 7.86 (s, 1H),7.81 (s, 1H), 7.49 (dd, 2H, J = 5.6, 8.8 Hz), 7.25-7.20 (m, 3H), 6.78(s, 1H), 6.70 (t, 1H, J = 54.8 Hz), 4.21-4.05 (m, 4H), 4.00-3.91 (m,4H), 3.84 (s, 3H). 120 2 ¹H-NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.04(s, 537 1H), 8.00 (d, 1H, J = 1.2 Hz), 7.87-7.86 (m, 2H), 7.34- 7.15 (m,6H), 4.22-4.04 (m, 6H), 3.91-3.80 (m, 8H), 3.512-3.46 (m, 1H), 2.99-2.52(m, 3H), 2.55-2.33 (m, 1H). 123 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.57(s, 2H), 8.04 (s, 573 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H),7.29-7.14 (m, 4H), 7.07-7.03 (m, 1H), 4.17-4.14 (m, 4H), 4.11-4.10 (m,2H), 4.02-4.00 (m, 4H), 3.73-3.71 (m, 2H), 3.42-3.37 (m, 1H), 2.77-2.59(m, 3H), 2.40-2.33 (m, 2H). 124 2 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s,2H), 7.85 (d, 601 J = 2.1 Hz, 2H), 7.52-7.37 (m, 2H), 7.19-7.03 (m, 3H),6.22 (s, 1H), 5.87 (s, 1H), 4.12-4.02 (m, 4H), 3.98 (br.s, 2H),3.94-3.81 (m, 4H), 3.52 (t, J = 5.8 Hz, 2H), 2.44 (br.s, 2H), 1.80 (s,3H).

Biochemical Activity of Compounds

In order to assess the activity of chemical compounds against therelevant kinase of interest, the Caliper Life Sciences electrophoreticmobility shift technology platform is used. Fluorescently labeledsubstrate peptide is incubated in the presence of kinase and ATP so thata reflective proportion of the peptide is phosphorylated. At the end ofthe reaction, the mix of phosphorylated (product) and non-phosphorylated(substrate) peptides are passed through the microfluidic system of theCaliper EZ Reader 2, under an applied potential difference. The presenceof the phosphate group on the product peptide provides a difference inmass and charge between those of the substrate peptide, resulting in aseparation of the substrate and product pools in the sample. As thepools pass a LEDS within the instrument, these pools are detected andresolved as separate peaks. The ratio between these peaks thereforereflects the activity of the chemical matter at that concentration inthat well, under those conditions.

KIT D816V assay at Km: In each well of a 384-well plate, 0.04 ng/ul (0.5nM) of D816V KIT (Carna Bioscience 08-156) was incubated in a total of12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM Srctide (5-FAM-GEEPLYWSFPAKKK-NH2) and 15 uM ATP at 25C for 90 minutes in the presence or absence of a dosed concentrationseries of compound (1% DMSO final concentration). The reaction wasstopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5,0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (CaliperLifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −700, downstream voltage−3000, post sample sip 35 s). Data was normalized to 0% and 100%inhibition controls and the IC₅₀ or EC₅₀ calculated using a 4-parameterfit using GraphPad Prism.

PDGFRA D842V assay at Km: In each well of a 384-well plate, 0.7 ng/ul (8nM) of PDGFRA D842V (ProQinase 0761-0000-1) was incubated in a total of12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM CSKtide (5-FAM-KKKKEEIYFFF-NH2) and 15 uM ATP at 25 Cfor 90 minutes in the presence or absence of a dosed concentrationseries of compound (1% DMSO final concentration). The reaction wasstopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5,0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (CaliperLifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −500, downstream voltage−3000, post sample sip 38 s). Data was normalized to 0% and 100%inhibition controls and the IC₅₀ or EC₅₀ calculated using a 4-parameterfit using GraphPad Prism.

Cellular Activity

HMC1.2 autophosphorylation assay: 10,000 HMC1.2 cells were incubated in22 ul culture media (phenol-red free IMDM, no serum) in each well of a384-well plate and serum starved overnight in a tissue culture incubator(5% CO₂, 37° C.). A 10-point dose concentration series of compound (25uM-95.4 pM) were then added to the cells in a volume of 3.1 ul to eachwell (0.25% DMSO final concentration). After 90 minutes, 6 ul of 5×AlphaLISA Lysis Buffer (Perkin Elmer) supplemented with a protease andphosphatase inhibitor cocktail (Cell Signaling Technologies) was addedto each well and shaken at 450 rpm for 15 minutes at 4° C. 10 ul ofphospho-Y719 c-KIT and total c-KIT antibodies (15 nM finalconcentration, Cell Signaling Technologies) and 50 ug/ml AlphaLISArabbit acceptor beads (Perkin Elmer) were added to each well and shakenat 300 rpm at room temperature for 2 hours. 10 ul of 100 ug/mlstreptavidin donor beads (Perkin Elmer) were added to each well, blockedfrom light with aluminum adhesive and shaken at 300 rpm at roomtemperature for 2 hours. Fluorescence signal was obtained on Envision(Perkin Elmer) by AlphaScreen 384 well HTS protocol. Data was normalizedto 0% and 100% inhibition controls and the IC50 was calculated usingFour Parameter Logistic IC50 curve fitting.

The Table below shows the activity of compounds in a Mast cell leukemiacell line, HMC 1.2. This cell line contains KIT mutated at positionsV560G and D816V resulting in constitutive activation of the kinase. Thefollowing compounds were tested in an assay to measure direct inhibitionof KIT D816V kinase activity by assaying KIT autophosphorylation attyrosine 719 on the KIT protein.

In the Table below, for biochemical D816V and D842V activity, thefollowing designations are used: <1.00 nM=A; 1.01-10.0 nM=B; 10.01-100.0nM=C; >100 nM=D; and ND=not determined. For cellular activity in theHMC1.2 cell line, the following designations are used: A means <50 nM; Bmeans ≥50 and <100 nM; C means ≥100 and <1000 nM; D means ≥1000 and lessthan 10000 nM; E means ≥10000 nM; and ND=not determined.

INH-KIT- Compound INH KIT INH PDFGRA PHOS- Number D816V D842V HMC1.2 1 D2 D E 3 C D 4 D E 5 C D 6 D E 7 A A B 8 B C 9 B B A 10 A A A 11 B C 12 AA 13 B C 14 A B A 15 C C 16 B C 17 B C 18 C C E 19 B C 20 B B A 21 B A B22 A A A 23 C C 24 B C 25 A A 26 A A A 27 B A 28 B A 29 B B B 30 A A A31 B A 32 B A 33 B C 34 A A B 35 A A A 36 B C 37 C D 38 B B B 39 B A A40 B C 41 B B B 42 C D 43 B A 44 A A A 45 A A A 46 A A A 47 A A 48 B A49 A A 50 B A 51 C 52 B C 53 C D 54 B C 55 C C 56 A A 57 A B A 58 A A 59C C 60 B A 61 B C 62 B B B 63 A A 64 C C 65 B B C 66 B C 67 C C 68 B B A69 B C 70 B A 71 B B 72 A A 73 B A 74 B B 75 A A 76 B B B 77 B A A 78 AA A 79 B A A 80 C 81 C D 82 C C 83 A A 84 B B A 85 A A 86 A A A 87 B B C88 A A 89 D D 90 D D 91 A B 92 B A 93 B A A 94 A A A 95 A B 96 A A A 97B B A 98 A A C 99 C D 100 A A A 101 C B 102 B B B 103 B C 104 B C 105 BA 106 B A 107 D D 108 D D 109 C C 110 B A 111 A A A 112 B C 113 A A 114A A 115 B A A 116 A A A 117 A B A 118 B C 119 C C 120 A B 121 A A A 122B B A 123 B B B 124 B A

Efficacy in an In Vivo Model

Compound 46 and Dasatinib were evaluated in a P815 mastocytoma xenograftmodel. P815 tumor cells (ATCC, Manassas, Va., cat #ATCC® TIB-64) weremaintained in vitro as a suspension and monolayer culture in RPMI1640medium supplemented with 10% fetal calf serum at 37° C. in an atmosphereof 5% CO₂ in air. The tumor cells were sub-cultured twice weekly bytrypsin-EDTA treatment. The cells growing in an exponential growth phasewere harvested and counted for tumor inoculation.

Female BALB/c nude mice were used for the study. Each mouse wasinoculated subcutaneously in the right flank with the P815 tumor cells(1×10⁶) in 0.1 ml of PBS for tumor development. The treatments werestarted on day 6 after tumor inoculation when the average tumor sizereached approximately 89 mm³. The testing article and vehicle wereadministrated to the mice according to the regimen shown below.

Dosing Dose Volume Dosing Group n Treatment (mg/kg) (ml/kg) RouteSchedule* 1 13 Vehicle 0 10 p.o. QD x 10 2 10 Dasatinib 25 10 p.o. BID x10 3 16 Compound 46 3 10 p.o. QD x 10 4 16 Compound 46 10 10 p.o. QD x10 5 16 Compound 46 30 10 p.o. QD x 10 6 16 Compound 46 100 10 p.o. QD x10 Note: *QD = once per day, BID = twice per day.

Tumor sizes were measured every other day in two dimensions using acaliper, and the volume was expressed in mm³ using the formula: V=0.5a×b² where a and b were the long and short diameters of the tumor,respectively. The tumor size was then used for calculations of both T-Cand T/C values. T-C was calculated with T as the median time (in days)required for the treatment group tumors to reach a predetermined size(e.g., 1000 mm³), and C as the median time (in days) for the controlgroup tumors to reach the same size. The T/C value (in percent) is anindication of antitumor effectiveness; T and C are the mean volumes ofthe treated and control groups, respectively, on a given day.

TGI was calculated for each group using the formula: TGI(%)=[1−(Ti−T0)/(Vi−V0)]×100; Ti is the average tumor volume of atreatment group on a given day, T0 is the average tumor volume of thetreatment group on the day of treatment start, Vi is the average tumorvolume of the vehicle control group on the same day with Ti, and V0 isthe average tumor volume of the vehicle group on the day of treatmentstart. Tumor weight was measured at the endpoint.

A statistical analysis of difference in tumor volume and tumor weightamong the groups was conducted on the data obtained at the besttherapeutic time point after the final dose (the 8^(th) day after thestart of treatment). A one-way ANOVA was performed to compare tumorvolume and tumor weight among groups. All data were analyzed using Prism5.0. p<0.05 was considered to be statistically significant.

Results. The tumor growth curves of different treatment groups are shownin FIG. 1. Data points represent group mean tumor volume, error barsrepresent standard error of the mean (SEM). As shown in FIG. 1, Compound46 was effective in inhibiting tumor growth. Increasing the dose ofCompound 46 enhanced the tumor inhibition efficiency.

The results of the body weight changes in the tumor bearing mice areshown in FIG. 2. Data points represent group mean body weight change.Error bars represent standard error of the mean (SEM). As shown in FIG.2, body weight change was limited to less than 5%, even at the higherdoses of Compound 46. In contrast, animals treated with vehicle orDasatinib lost more than 5% body weight.

Thus, Compound 46, as a single agent, produced an observable antitumoractivity against the P815 mouse mastocytoma cancer xenograft model inthis study. In addition, the compound was well tolerated by thetumor-bearing animals, as demonstrated by lack of weight loss.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A method of treating melanoma in a patient in need thereof, whereinthe method comprises administering to the patient a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein W is selectedfrom hydrogen and

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl and heterocyclyl; each X and Y isindependently selected from CR¹ and N; Z is selected from C₁-C₆ alkyl,cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl,monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl,and monocyclic or bicyclic heterocyclylalkyl; wherein each of C₁-C₆alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclicaralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclicheterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independentlysubstituted with 0-5 occurrences of R^(C); L is selected from a bond,—(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-, —(C₂-C₆ alkenylene)-, —(C₁-C₆haloalkylene)-, —(C₁-C₆ heteroalkylene)-, —(C₁-C₆ hydroxyalkylene)-,—C(O)—, —O—, —S—, —S(O), —S(O)₂—, —N(R²)—, —O—(C₁-C₆ alkylene)-, —(C₁-C₆alkylene)-O—, —N(R²)—C(O)—, —C(O)—N(R²)—, —(C₁-C₆ alkylene)-N(R²)—,—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—C(O)—(C₁-C₆ alkylene)-,—C(O)—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—S(O)₂—, —S(O)₂—N(R²)—,—N(R²)—S(O)₂—(C₁-C₆ alkylene)-, and —S(O)₂—N(R²)—(C₁-C₆ alkylene)-; eachR^(A) and R^(B) is independently selected from C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ heterocyclyl, halo, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic or bicyclic aralkyl,—N(R²)(R²), cyano, and —OR²; each R^(C) is independently selected fromC₁-C₆ alkyl, C₁-C₆ alkynyl, halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic or bicyclicaryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl,monocyclic or bicyclic heterocyclyl, monocyclic or bicyclicheterocyclylalkyl, nitro, cyano, —C(O)R², —OC(O)R², —C(O)OR², —SR²,—S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆ alkylene)-S(O)₂—N(R²)(R²),—N(R²)(R²), —C(O)—N(R²)(R²), —N(R²)(R²)—C(O)R², —(C₁-C₆alkylene)-N(R²)—C(O)R², —NR²S(O)₂R², —P(O)(R²)(R²), and —OR²; whereineach of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl,aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independentlysubstituted with 0-5 occurrences of R^(a); or 2 R^(C) together with thecarbon atom(s) to which they are attached form a cycloalkyl orheterocyclyl ring substituted with 0-5 occurrences of R^(a); each ofR^(D) and R^(F) is independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ cycloalkyl, hydroxyl, halo, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,—N(R²)(R²), and cyano; each R¹ is independently selected from hydrogen,C₁-C₆ alkyl, monocyclic aralkyl, C₁-C₆ hydroxyalkyl, halo, C₁-C₆haloalkyl, —N(R²)(R²), and —OR²; each R² is independently selected fromhydrogen, hydroxyl, halo, thiol, C₁-C₆ thioalkyl, —NR″R″, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each ofC₁-C₆ alkyl, cycloalkyl and heterocyclyl is independently substitutedwith 0-5 occurrences of R^(b), or 2 R² together with the atoms to whichthey are attached form a cycloalkyl or heterocyclyl ring; each R^(a) andR^(b) is independently selected from hydrogen, halo, cyano, hydroxyl,C₁-C₆ alkoxyl, —C(O)R′, C(O)OR′, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, C₁-C₆ hydroxyalkyl, —NR′R′, and cycloalkyl, whereincycloalkyl is substituted with 0-5 occurrences of R′; each R′ ishydrogen, hydroxyl, or C₁-C₆ alkyl; each R″ is hydrogen, C₁-C₆ alkyl,—C(O)—C₁-C₆ alkyl, —C(O)—NR′R′; or —C(S)—NR′R′; and m, p, and q are eachindependently 0, 1, 2, 3, or
 4. 2. The method of claim 1, wherein thecompound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein at least one of X and Y is N.
 5. (canceled)
 6. The method ofclaim 1, wherein L is —(C(R²)(R²))_(m)—.
 7. The method of claim 1,wherein A is monocyclic or bicyclic aryl.
 8. The method of claim 1,wherein Z is monocyclic or bicyclic aryl.
 9. The method of claim 1,wherein Z is monocyclic or bicyclic heteroaryl.
 10. The method of claim1, wherein Z is monocyclic heteroaryl.
 11. The method of claim 1,wherein Z is selected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl,and pyridyl.
 12. The method of claim 1, wherein Z is phenyl.
 13. Themethod of claim 1, wherein Z is monocyclic or bicyclic heterocyclyl. 14.The method of claim 1, wherein R^(A) is fluoro and q is
 1. 15. A methodof treating melanoma in a patient in need thereof, wherein the methodcomprises administering to the patient a therapeutically effectiveamount of a compound selected from the group consisting of the compoundsbelow, or a pharmaceutically acceptable salt thereof: Compound NumberStructure 1

2

4

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

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68

69

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95

96

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101

102

103

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107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

16.-19. (canceled)
 20. The method of claim 1, wherein the patient has amutation in Exon 17 in KIT.
 21. The method of claim 20, wherein thepatient has a D816 mutation in KIT in Exon
 17. 22. The method of claim21, wherein the D816 mutation is D816V. 23.-24. (canceled)
 25. A methodof treating systemic mastocytosis in a patient in need thereof, whereinthe systemic mastocytosis is selected from aggressive systemicmastocytosis (ASM), SM with associated hematologic non-mast cell lineagedisease (SM-AHNMD), and mast cell leukemia, wherein the method comprisesadministering to the patient once daily i) 200-300 mg of a compoundwhich is:

or a pharmaceutically acceptable salt thereof, or ii) a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and 200-300mg of the compound or a pharmaceutically acceptable salt thereof.26.-31. (canceled)
 32. The method of claim 25, wherein the patient isadministered once daily i) 200 mg of the compound or a pharmaceuticallyacceptable salt thereof; or ii) a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and 200 mg of the compound or apharmaceutically acceptable salt thereof.